Hot topics in pharmacology archive

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2017

December 2017

Trends in GPCR drug discovery: new agents, targets and indications

Comments by Alexander Hauser and David Gloriam, University of Copenhagen and GPCRdb

New avenues for GPCR drug discovery have emerged owing to recent advances in receptor pharmacology, technological breakthroughs in structural biology and innovations in biotechnology. A collaboration between the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team) and the Uppsala University have published a detailed analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications [1]. Read the full article on our blog

Hauser AS et al. (2017). Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov., 16(12):829-842. doi: 10.1038/nrd.2017.178. [PMID:29075003]


Noncoding RNAs: Master Regulators of Inflammatory Signaling
(1) Chew CL et al. (2017). Noncoding RNAs: Master Regulators of Inflammatory Signaling. Trends in Molecular Medicine, doi:10.1016/j.molmed.2017.11.003. [Epub ahead of print] [Full text]


Refining The Accuracy Of Validated Target Identification Through Coding Variant Fine-Mapping In Type 2 Diabetes
(1) Mahajan A et al. (2017). Refining The Accuracy Of Validated Target Identification Through Coding Variant Fine-Mapping In Type 2 Diabetes. bioRxiv, doi: 10.1101/144410. [Epub ahead of print] [Full text]


Genetic architecture: the shape of the genetic contribution to human traits and disease
(1) Timpson NJ et al. (2017). Genetic architecture: the shape of the genetic contribution to human traits and disease. Nat Rev Genet., doi: 10.1038/nrg.2017.101. [Epub ahead of print] [29225335]


G Protein-Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus.
(1) Riddy DM et al. (2017). G Protein-Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus. Pharmacol Rev., 70(1):39-67. doi: 10.1124/pr.117.014373. [29233848]


The rise and fall of a scaffold: A trend analysis of scaffolds in the medicinal chemistry literature
(1) Zdrazil B, Guha R. (2017). The rise and fall of a scaffold: A trend analysis of scaffolds in the medicinal chemistry literature. J Med Chem, doi: 10.1021/acs.jmedchem.7b00954. [Epub ahead of print] [29235859]


Objective, Quantitative, Data-Driven Assessment of Chemical Probes
(1) Antolin AA et al. (2017). Objective, Quantitative, Data-Driven Assessment of Chemical Probes. Cell Chemical Biology, doi:10.1016/j.chembiol.2017.11.004. [Epub ahead of print] [Full text]


A snapshot of 3649 Web-based services published between 1994 and 2017 shows a decrease in availability after 2 years
(1) Osz Á et al. (2017). A snapshot of 3649 Web-based services published between 1994 and 2017 shows a decrease in availability after 2 years. Brief Bioinform., doi: 10.1093/bib/bbx159. [Epub ahead of print] [29228189]


Science Forum: The Human Cell Atlas
(1) Regev A et al. (2017). Science Forum: The Human Cell Atlas. Elife, 6. pii: e27041. doi: 10.7554/eLife.27041. [Epub ahead of print] [29206104]


Matching disease and phenotype ontologies in the ontology alignment evaluation initiative
(1) Harrow I et al. (2017). Matching disease and phenotype ontologies in the ontology alignment evaluation initiative. J Biomed Semantics., 8(1):55. doi: 10.1186/s13326-017-0162-9. [PMID:29197409]


Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms
(1) Jespers W et al. (2017). Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms. Trends Pharmacol Sci., pii: S0165-6147(17)30218-3. doi: 10.1016/j.tips.2017.11.001. [Epub ahead of print] [PMID:29203139]


Pharma's broken business model: An industry on the brink of terminal decline
(1) Stott K. (2017). Pharma's broken business model: An industry on the brink of terminal decline. [Blog]


The Promise & Peril in YOUR Genes
(1) Green R. (2017). The Promise & Peril in YOUR Genes. [Podcast]


Structural coverage of the proteome for pharmaceutical applications
(1) Somody JC et al. (2017). Structural coverage of the proteome for pharmaceutical applications. Drug Discov Today, 22(12):1792-1799. doi: 10.1016/j.drudis.2017.08.004. [PMID:28843631]


The target landscape of clinical kinase drugs
(1) Klaeger S et al. (2017). The target landscape of clinical kinase drugs. Science, 358(6367). pii: eaan4368. doi: 10.1126/science.aan4368. [PMID:29191878]


Post-transcriptional regulation across human tissues
(1) Franks A et al. (2017). Post-transcriptional regulation across human tissues. PLoS Comput Biol., 13(5):e1005535. doi: 10.1371/journal.pcbi.1005535. [PMID:28481885]


Mechanistic enzymology in drug discovery: a fresh perspective
(1) Holdgate GA et al. (2017). Mechanistic enzymology in drug discovery: a fresh perspective. Nat Rev Drug Discov., doi: 10.1038/nrd.2017.219. [Epub ahead of print] [PMID:29192286]


A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles
(1) Subramanian A et al. (2017). A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell., 171(6):1437-1452.e17. doi: 10.1016/j.cell.2017.10.049. [PMID:29195078]


Five ways to fix statistics
(1) Leek J et al. (2017). Five ways to fix statistics. Nature., 9551(7682):557-559. doi: 10.1038/d41586-017-07522-z. [PMID:29189798]


The CompTox Chemistry Dashboard: a community data resource for environmental chemistry
(1) Williams AJ et al. (2017). The CompTox Chemistry Dashboard: a community data resource for environmental chemistry. J Cheminform., 9(1):61. doi: 10.1186/s13321-017-0247-6. [PMID:29185060]


November 2017

Boehringer Ingelheim shares well-characterized pre-clinical molecules with the scientific community at opnMe.com
(1) https://www.opnme.com/molecules


Visualizing the GPCR Network: Classification and Evolution
(1) Hu GM et al. (2017). Visualizing the GPCR Network: Classification and Evolution. Sci Rep., 7(1):15495. [PMID:29138525]


PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes
(1) Ben Nasr M et al. (2017). PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes. Sci Transl Med., 9(416). pii: eaam7543. [PMID:29141886]


A simple proposal for the publication of journal citation distributions
(1) Lariviere V et al. (2016). A simple proposal for the publication of journal citation distributions. bioRxiv, doi: https://doi.org/10.1101/062109. [Epub ahead of print]. [Abstract]


Improving virtual screening of G protein-coupled receptors via ligand-directed modeling
(1) Coudrat T et al. (2017). Improving virtual screening of G protein-coupled receptors via ligand-directed modeling. PLoS Comput Biol., 13(11):e1005819. doi: 10.1371/journal.pcbi.1005819. [Epub ahead of print]. [PMID:29131821]


GPCRdb in 2018: adding GPCR structure models and ligands
(1) Pándy-Szekeres G et al. (2017). GPCRdb in 2018: adding GPCR structure models and ligands. Nucleic Acids Res., doi: 10.1093/nar/gkx1109. [Epub ahead of print]. [PMID:29155946]


Gαi is required for carvedilol-induced β1 adrenergic receptor β-arrestin biased signaling
(1) Wang J et al. (2017). Gαi is required for carvedilol-induced β1 adrenergic receptor β-arrestin biased signaling. Nat Commun., 8(1):1706. [PMID:29167435]


Cryo-EM structures of Mucolipin TRP Channels in the Lysosome: Five Together at Once

Comments by Haoxing Xu, NC-IUPHAR subcommittee Chair of the Transient Receptor Potential Channels and Professor, the University of Michigan

Five independent studies, led by Youxing Jiang, Xiaochun Li, Soek-yong Lee, Maojun Yang, and Jian Yang, respectively, report a total of three TRPML1 and two TRPML3 Cryo-EM structures, all at atomic resolution, and in both closed and agonist-bound open conformations [1-5]. Read the full article on our blog

  1. Zhou X et al. (2017). Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. Nat Struct Mol Biol, doi: 10.1038/nsmb.3502. [Epub ahead of print] [PMID:9106414]
  2. Zhang S et al. (2017). Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism. Protein Cell, 8(11):834-847 [PMID:28936784]
  3. Schmiege P et al. (2017). Human TRPML1 channel structures in open and closed conformations. Nature, 550(7676):366-370. [PMID:29019983]
  4. Hirschi M et al. (2017). Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature, 550(7676):411-414 [PMID:29019979]
  5. Chen Q et al. (2017). Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature, 550(7676):415-418. [PMID:29019981]

RNA as a small molecule druggable target
(1) Rizvi NF and Smith GF. (2017). RNA as a small molecule druggable target. Bioorg Med Chem lett., 27(23):5083-5088 [PMID:29097169]


Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors
(1) Dahlin JL et al. (2017). Assay interference and off-target liabilities of reported histone acetyltransferase inhibitors. Nat Commun., 8(1):1527 [PMID:29142305]


Region and cell-type resolved quantitative proteomic map of the human heart
(1) Doll S et al. (2017). Region and cell-type resolved quantitative proteomic map of the human heart. Nat Commun., 8(1):1469 [PMID:29133944]


Architecture of the human interactome defines protein communities and disease networks
(1) Huttlin EL et al. (2017). Architecture of the human interactome defines protein communities and disease networks. Nature, 545(7655):505-509 [PMID:28514442]


Drug target ontology to classify and integrate drug discovery data
(1) Lin Y et al. (2017). Drug target ontology to classify and integrate drug discovery data. J Biomed Semantics, 8(1):50 [PMID:29122012]


Extending the Structural View of Class B GPCRs
(1) de Graaf C et al. (2017). Extending the Structural View of Class B GPCRs. Trends in Biomedical Sciences, S0968-0004(17)30188-3. doi: 10.1016/j.tibs.2017.10.003. [Epub ahead of print] [PMID:29132948]


Structure-Based Design and Discovery of New M2 Receptor Agonists
(1) Fish I et al. (2017). Structure-Based Design and Discovery of New M2 Receptor Agonists. J Med Chem, doi: 10.1021/acs.jmedchem.7b01113. [Epub ahead of print] [PMID:29094937]


The structural basis of ryanodine receptor ion channel function
(1) Meissner G. (2017). The structural basis of ryanodine receptor ion channel function. J. Gen. Physiol., doi: 10.1085/jgp.201711878. [Epub ahead of print] [PMID:29122978]


Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications
(1) Shih HP et al. (2017). Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications. Nat Rev Drug Discov., doi: 10.1038/nrd.2017.194. [Epub ahead of print] [PMID:29075002]


October 2017

Directing evolution: the next revolution in drug discovery?
(1) Davis AM et al. (2017). Directing evolution: the next revolution in drug discovery? Nat Rev Drug Discov., 16(10):681-698. doi: 10.1038/nrd.2017.146 [PMID:28935911]


Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications
(1) Shih HP et al. (2017). Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications. Nat Rev Drug Discov., 7(1):13741. doi: 10.1038/nrd.2017.194. [Epub ahead of print] [PMID:29075002]


A single extracellular amino acid in Free Fatty Acid Receptor 2 defines antagonist species selectivity and G protein selection bias
(1) Sergeev E et al. (2017). A single extracellular amino acid in Free Fatty Acid Receptor 2 defines antagonist species selectivity and G protein selection bias. Sci Rep., 7(1):13741. doi: 10.1038/s41598-017-14096-3. [PMID:29061999]


Imagining the "open" university: Sharing scholarship to improve research and education
(1) McKiernan EC. (2017). Imagining the "open" university: Sharing scholarship to improve research and education. PLoS Biol., 15(10):e1002614. doi: 10.1371/journal.pbio.1002614. [PMID:29065148]


Human gene essentiality
(1) Bartha I et al. (2017). Human gene essentiality. Nature Reviews Genetics, doi:10.1038/nrg.2017.75 [Epub ahead of print] [Full text]


D4 dopamine receptor high-resolution structures enable the discovery of selective agonists
(1) Wang S et al. (2017). D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science, 358(6361):381-386. doi: 10.1126/science.aan5468. [PMID:29051383]


Discovery of new GPCR ligands to illuminate new biology
(1) Roth BL et al. (2017). Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol., 13(11):1143-1151. doi: 10.1038/nchembio.2490. [PMID:29045379]


Human genomics: Cracking the regulatory code
(1) Ward MC & Gilad Y. (2017). Human genomics: Cracking the regulatory code. Nature. News & Views, 550:190-191, doi:10.1038/550190a. [Nature: News & views]


Structural Basis for G Protein-Coupled Receptor Activation
(1) Maglik A & Kruse AC. (2017). Structural Basis for G Protein-Coupled Receptor Activation. Biochemistry, doi: 10.1021/acs.biochem.7b00747. [Epub ahead of print] [PMID:28967738]


The Human Protein Atlas - A spatial map of the human proteome
(1) Thul PJ & Lindskog C. (2017). The Human Protein Atlas - A spatial map of the human proteome. Protein Sci., doi: 10.1002/pro.3307. [Epub ahead of print] [PMID:28940711]


Functional characterization of 3D-protein structures informed by human genetic diversity
(1) Hicks M et al. (2017). Functional characterization of 3D-protein structures informed by human genetic diversity.bioRxiv., https://doi.org/10.1101/182287. [bioRxiv: Abstract]


Obesity: Receptors identified for a weight regulator
(1) Saarma M & Goldman A. (2017). Obesity: Receptors identified for a weight regulator. Nature. News & Views, doi:10.1038/nature24143. [Nature: News & views]


The drug-maker's guide to the galaxy
(1) Mullard A. (2017). The drug-maker's guide to the galaxy. Nature, 549(7673):445-447 doi:10.1038/549445a. [PMID: News Feature]


September 2017

CHEMGENIE: integration of chemogenomics data for applications in chemical biology
(1) Kutchukian PS et al. (2017). CHEMGENIE: integration of chemogenomics data for applications in chemical biology. Drug Discov Today., pii: S1359-6446(17)30102-2. doi: 10.1016/j.drudis.2017.09.004. [Epub ahead of print] [PMID:28917822]


A new research avenue investigating mitochondrial GPCR biology

Comments by Michael Spedding, Secretary General, IUPHAR, and CEO, Spedding Research Solutions SARL, France

As one of the first propositions for GPCRs being present in mitochondrial membranes, a recent report from Robert Friedlander and colleagues [1] follows on from previous work characterising synaptic and extrasynaptic mitochondria in human cortex (post-mortem samples) and their role in neuroprotection. This work, if reproduced, opens up new vistas, and has many implications for neurodegenerative diseases. Taken together, Suofu et al. show that melatonin is synthesised in mitochondria, that MT1 receptors are present in mitochondrial membranes, and that MT1 receptor stimulation reduces cytochrome c and caspase secretion caused by calcium overload. The authors propose that this is a mechanism for the neuroprotective effects of melatonin in hypoxic-ischaemic brain injury in neonatal and in models of Huntington’s disease, where there is mitochondrial impairment. Read the article on our blog

(1) Suofu Y et al. (2017). Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci U S A., 114(38):E7997-E8006. doi: 10.1073/pnas.1705768114. [PMID:28874589]


Receptor Quaternary Organization Explains G Protein-Coupled Receptor Family Structure
(1) Felce JH et al. (2017). Receptor Quaternary Organization Explains G Protein-Coupled Receptor Family Structure. Cell Rep., 20(11):2654-2665. [PMID:28903045]


Understanding enzyme function evolution from a computational perspective
(1) Tyzack JD et al. (2017). Understanding enzyme function evolution from a computational perspective. Curr Opin Struct Biol., 47:131-139. [PMID:28892668]


Protein maps chart the causes of disease
(1) Fessenden M. (2017). Protein maps chart the causes of disease. Nature, 549(7671):293-295. [PMID:28905898]


Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway
(1) Benson H et al. (2017). Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway. Br J Pharmacol., doi: 10.1111/bph.14037. [Epub ahead of print] [PMID:28910500]


A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia
(1) Suply T et al. (2017). A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia. Sci Signal., 10(496). pii: eaal0180. [PMID:28900043]


Structural and Functional View of Polypharmacology
(1) Moya-García A et al. (2017). Structural and Functional View of Polypharmacology. Sci Rep., 7(1):10102. [PMID:28860623]


The T cell antigen receptor: the Swiss army knife of the immune system
(1) Attaf M et al. (2017). The T cell antigen receptor: the Swiss army knife of the immune system. Clin Exp Immunol., 181(1):1-18. [PMID:25753381]


Crystal structure of LPA6, a receptor for lysophosphatidic acid, at 3.2A

Comments by Jerold Chun (Neuroscience Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA)

Lysophospholipids (LPs) have myriad roles as extracellular signals that activate cognate G protein-coupled receptors (GPCRs) (2). LPs for which receptors have been reported include lysophosphatidic acid (LPA) (receptors: LPA1-6), sphingosine 1-phosphate (S1P1-5), lysophosphatidyl serine (LPS1-3, 2L (2L is a pseudogene in humans)) and lysophosphatidyl inositol/glucose (LPI/LPG), all of which are Class A GPCRs. Of these 15 LP receptors, crystal structures of two have been previously reported for S1P1 (2.8-3.35A) (3) and LPA1 (2.9-3.0A) (4) both of which utilized human cDNA sequences bound in the presence of antagonists. The new structure (1), from the laboratories of Junken Aoki and Osamu Nureki, elucidates a zebrafish receptor – with 80% amino acid similarity to human LPA6, in the transmembrane (TM) region - in the absence of a ligand, which nonetheless crystalized. This contrasts with the prior 2 antagonist-bound human structures. All 3 receptors were chimeric proteins stabilized by T4-lysozyme (S1P1 and LPA6) or thermostabilized apocytochrome b562RIL (LPA1) fused to the 3rd intracellular loop, but all were capable of responding to native ligands. Read the full article on our blog

(1) Taniguchi R et al. (2017). Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6. Nature, 548: 356-360. [PMID:28792932]
(2) Kihara Y et al. (2014) Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br J Pharmacol, 171: 3575-3594. [PMID:24602016]
(3) Hanson MA et al. (2012) Crystal structure of a lipid G protein-coupled receptor. Science, 335: 851-855. [PMID:22344443]
(4) Chrencik JE et al. (2015) Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1. Cell, 161: 1633-1643. [PMID:26091040]


Comparing structural and transcriptional drug networks reveals signatures of drug activity and toxicity in transcriptional responses
(1) Sirci F et al. (2017). Comparing structural and transcriptional drug networks reveals signatures of drug activity and toxicity in transcriptional responses. NPJ Syst Biol Appl., 3:23. [PMID:28861278]


Commensal bacteria make GPCR ligands that mimic human signalling molecules
(1) Cohen LJ et al. (2017). Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature, doi: 10.1038/nature23874. [Epub ahead of print] [PMID:28854168]


In silico prediction of novel therapeutic targets using gene–disease association data
(1) Ferrero E et al. (2017). In silico prediction of novel therapeutic targets using gene–disease association data. J Transl Med., 15(1):182. [PMID:28851378]


An atlas of B-cell clonal distribution in the human body
(1) Meng W et al. (2017). An atlas of B-cell clonal distribution in the human body. Nat Biotechnol., doi: 10.1038/nbt.3942. [Epub ahead of print] [PMID:28829438]


Functional characterization of 3D-protein structures informed by human genetic diversity
(1) Hicks M et al. (2017). Functional characterization of 3D-protein structures informed by human genetic diversity. bioRxiv, doi:10.1101/182287. [Epub ahead of print] [Abstract]


GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates
(1) Mullican SE et al. (2017). GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med., doi: 10.1038/nm.4392. [Epub ahead of print] [PMID:28846097]


Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs.
(1) Congreve M et al. (2017). Applying Structure-Based Drug Design Approaches to Allosteric Modulators of GPCRs. Trends Pharmacol Sci., 38(9):837-847. [PMID:28648526]


Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure
(1) Liu X et al. (2017). Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure. Nature, 548(7668):480-484 [PMID:28813418]


Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
(1) Ridker PM et al. (2017). Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med., doi: 10.1056/NEJMoa1707914. [Epub ahead of print] [PMID:28845751]


Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage.
(1) Petrucci V et al. (2017). Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. Sci Rep., 25;7(1):9560. [PMID:28842619]


August 2017

FZD6 dimers dissociate after stimulation – briefly

Comments by Nevin A. Lambert (Department of Pharmacology and Toxicology Medical College of Georgia, Augusta University, USA)

GPCRs of all classes are widely thought to form homodimers, heterodimers and higher-order oligomers. The functional significance of dimerization is well understood for Class C receptors but less certain for the other GPCR classes, including the rather unconventional class F or Frizzled (FZD) receptors. Although the relationship between receptor activity and quaternary structure is often unclear, across classes it is generally found that ligand binding does not dramatically influence dimerization. A recent report by Gunnar Schulte and his colleagues suggests that in this respect class F receptors may once again be somewhat different [1]. Using an impressive combination of live-cell imaging, biochemical and modeling techniques the group presents evidence that FZD6 forms relatively stable dimers that dissociate when stimulated with the activating ligand WNT-5A. Remarkably, FZD6 protomers reassociate at the cell surface after 20 minutes of continuous stimulation, a timing which coincides with termination of ERK1/2 phosphorylation. Read the full article on our blog

(1) Petersen J et al. (2017) Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling. Nat Commun., 8(1):226. [PMID:28790300]


FTBMT, a novel and selective GPR52 agonist, demonstrates antipsychotic-like and procognitive effects in rodents revealing a potential therapeutic agent for schizophrenia.
(1) Nishiyama K et al. (2017). FTBMT, a novel and selective GPR52 agonist, demonstrates antipsychotic-like and procognitive effects in rodents revealing a potential therapeutic agent for schizophrenia. Journal of Pharmacology and Experimental Therapeutics, DOI: 10.1124/jpet.117.242925 [Epub ahead of print] [Abstract]


Anti-inflammatory therapies for cardiovascular disease
(1) Ridker PM and Lüscher TF. (2014). Anti-inflammatory therapies for cardiovascular disease. Eur Heart J., 35(27):1782-91. [PMID:24864079]


A Review of Recent Advances in Translational Bioinformatics: Bridges from Biology to Medicine
(1) Vamathevan J and Birney E. (2017). A Review of Recent Advances in Translational Bioinformatics: Bridges from Biology to Medicine. Yearbook of Medical Informatics, 26(1):178-187. [Abstract]


The 10,000 Immunomes Project: A resource for human immunology
(1) Zalocusky KA et al. (2017). The 10,000 Immunomes Project: A resource for human immunology. bioRxiv., doi: https://doi.org/10.1101/180489. [bioRxiv:180489]


Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors
(1) Irving A et al. (2017). Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors. Adv. Pharmacol., 80:223-247. [PMID:28826536]


Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis
(1) Stsiapanava A et al. (2017). Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis. PNAS USA., 114(36):9689-9604. [PMID:28827365]


Settling the score: variant prioritization and Mendelian disease
(1) Ellbeck K et al. (2017). Settling the score: variant prioritization and Mendelian disease. Nat Rev. Genetics., DOI: 10.1038/nrg.2017.52 [Epub ahead of print]. [PMID:28804138]


A kinetic view of GPCR allostery and biased agonism
(1) Lane R et al. (2017). A kinetic view of GPCR allostery and biased agonism. Nat Chem Biol., 13(9):929-937. [PMID:28820879]


A pathology atlas of the human cancer transcriptome
(1) Uhlen M et al. (2017). A pathology atlas of the human cancer transcriptome. Science., d357(6352). pii: eaan2507. [PMID:28818916]


X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog
(1) Shihoya W et al. (2017). X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. Nat Struct Mol Biol., doi: 10.1038/nsmb.3450. [Epub ahead of print] [PMID:28805809]


The immunopathology of sepsis and potential therapeutic targets
(1) van der Poll T et al. (2017). The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol., 17(7):407-420. [PMID:28436424]


The PI3K Pathway in Human Disease
(1) Fruman DA et al. (2017). The PI3K Pathway in Human Disease. Cell, 170(4):605-635. [PMID:28802037]


Diabetic nephropathy - is this an immune disorder?
(1) Tesch GH. (2017). Diabetic nephropathy - is this an immune disorder? Clin Sci (Lond)., 131(16):2183-2199. [PMID:28760771]


Psychosis: an autoimmune disease?
(1) Al-Diwani AAJ et al. (2017). Psychosis: an autoimmune disease? Immunology, doi:10.1111/imm.12795. [Epub ahead of print] [28704576]


Identification of essential genes for cancer immunotherapy
(1) Patel SJ et al. (2017). Identification of essential genes for cancer immunotherapy. Nature, doi: 10.1038/nature23477. [Epub ahead of print] [PMID:28783722]


Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects
(1) Zhou Y et al. (2017). Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin Pharmacol Ther., doi: 10.1002/cpt.690. [Epub ahead of print] [PMID:28378927]


The new alchemy: Online networking, data sharing and research activity distribution tools for scientists
(1) Williams AJ et al. (2017). The new alchemy: Online networking, data sharing and research activity distribution tools for scientists. F1000Research, 6:1315. [Abstract]


In Silico Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetics (ADME-PK): Utility and Best Practices
(1) Lombardo F et al. (2017). In Silico Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetics (ADME-PK): Utility and Best Practices. An Industry Perspective from the International Consortium for Innovation through Quality in Pharmaceutical Development. J Med Chem., doi: 10.1021/acs.jmedchem.7b00487. [Epub ahead of print] [PMID:28609624]


Calls grow to tap the gold mine of human genetic knockouts
(1) Mullard A. (2017). Calls grow to tap the gold mine of human genetic knockouts. Nat Rev Drug Discov., 16(8):515-518. [PMID:28757624]


A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression
(1) Gupta RM et al. (2017). A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression. Cell, 170(3):522-533.e15. [PMID:28753427]


Objective, Quantitative, Data-Driven Assessment of Chemical Probes
(1) Antolin AA et al. (2017). Objective, Quantitative, Data-Driven Assessment of Chemical Probes. bioRxiv, doi:10.1101/168369 [Epub ahead of print] [Abstract]


Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology.
(1) Blagg J, Workman P. (2017). Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology. Cancer Cell, 32(1):9-25. [PMID:28697345]


How Ligands Illuminate GPCR Molecular Pharmacology.
(1) Wacker D et al. (2017). How Ligands Illuminate GPCR Molecular Pharmacology. Cell, 170(3):414-427. [PMID:28753422]


Redefine Statistical Significance
(1) Benjamin D et al. (2017). Redefine Statistical Significance. PsyArXiv, doi:10.17605/OSF.IO/MKY9J. [Epub ahead of print] [Abstract]


Translating New Science Into the Drug Review Process
(1) Rouse R et al. (2017). Translating New Science Into the Drug Review Process. Therapeutic Innovation & Regulatory Science, doi:10.1177/2168479017720249. [Epub ahead of print] [Abstract]


July 2017

Channel opening and gating mechanism in AMPA-subtype glutamate receptors
(1) Twomey EC et al. (2017). Channel opening and gating mechanism in AMPA-subtype glutamate receptors. Nature, doi: 10.1038/nature23479. [Epub ahead of print] [PMID:28737760]


A cryptic binding pocket in K2P2 exposes new avenues for drug development

Comments by Leigh D. Plant (Research Associate Professor, School of Pharmacy, Northeastern University)

The TREK subfamily of K2P channels (K2P2, K2P4 and K2P10) pass background potassium currents that modulate the excitability of neuronal cells and cardiac myocytes. In recent years, these channels have received significant attention as potential drug targets. In an elegant new study, Lolicato and colleagues from the Minor lab highlight the synergistic power of combining structural and functional approaches to reveal new insights into the operation of membrane proteins and unveil a new avenue for the development of TREK-channel pharmacology [1]. Read the full article on our blog

(1) Lolicato M et al. (2017). K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site. Nature, 547(7663):364-368. [PMID:28693035]


Opportunities for therapeutic antibodies directed at G-protein-coupled receptors
(1) Hutchings CJ et al. (2017). Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat Rev Drug Discov., doi: 10.1038/nrd.2017.91. [Epub ahead of print] [PMID:28706220]


Information Retrieval and Text Mining Technologies for Chemistry
(1) Krallinger M et al. (2017). Information Retrieval and Text Mining Technologies for Chemistry. Chem Rev., 117(12):7673-7761. [PMID:28475312]


Genome-wide genetic data on ~500,000 UK Biobank participants
(1) Bycroft C et al. (2017). Genome-wide genetic data on ~500,000 UK Biobank participants. bioRxiv, 166298, doi:10.1101/166298. [Epub ahead of print] [Abstract]


Structure and function of peptide-binding G protein-coupled receptors
(1) Wu F et al. (2017). Structure and function of peptide-binding G protein-coupled receptors. J Mol Biol., doi: 10.1016/j.jmb.2017.06.022. [Epub ahead of print] [PMID:28705763]


Structures of Human A1 and A2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity
(1) Cheng RKY et al. (2017). Structures of Human A1 and A2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity. Cell, doi: 10.1016/j.str.2017.06.012 [Epub ahead of print] [Full text]


Phantom PAINS: Problems with the Utility of Alerts for Pan-Assay INterference CompoundS
(1) Capuzzi SJ et al. (2017). Phantom PAINS: Problems with the Utility of Alerts for Pan-Assay INterference CompoundS. J Chem Inf Model., 57(3):417-427 [PMID:28165734]


Text mining of 15 million full-text scientific articles
(1) Westergaard D et al. (2017). Text mining of 15 million full-text scientific articles. bioRxiv., doi: 10.1101/162099 [Epub ahead of print] [Abstract]


How to build a human cell atlas.
(1) Nowogrodzki A. (2017). How to build a human cell atlas. Nature, 547(7661):24-26. [PMID:28682347]


Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology
(1) Blagg J, Workman P. (2017). Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology. Cancer Cell, 32(1):9-25. [PMID:28697345]


Insufficient antibody validation challenges oestrogen receptor beta research
(1) Andersson S. (2017). Insufficient antibody validation challenges oestrogen receptor beta research. Nat Commun., 8:15840. [PMID:28643774]


Agonist-bound crystal structures of the CB1 cannabinoid receptor

Comments by Lahari Murali (@wavesml), Steve Alexander (@mqzspa), Steven Doughty and Abi Emtage (@AbiEmtage)

Antagonist bound crystal structures of GPCRs are useful in giving an insight into the molecular conformation of a receptor's inactive state whilst enabling the design of new drugs. However, they prove insufficient to understand the activation mechanism of the receptor and mediation of its physiological effects. This necessitates the study of agonist-bound structures. In this direction, Hua et al., (2017) [1] have recently reported two agonist-bound crystal structures of Cannabinoid Receptor 1 (CB1), one with a tetrahydrocannabinol derivative, AM11542 [PDB: 5XRA], and the other with a hexahydrocannabinol, AM841 [PDB: 5XR8]. Read the full article on our blog

(1) Hua, T. et al. (2017). Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature. doi:10.1038/nature23272. [PMID: 28678776]


Identifiers for the 21st century

Comments by Chris Southan (@cdsouthan)

While identifiers are not a traditional “hot topic” in pharmacology the subject is becoming increasingly important. One of the reasons is that for mechanistic pharmacology the community needs to define (and communicate) identifiers for the key entities of model organism species and strains, proteins, protein complexes, genes, sequences sequence variants, as well as the explicit molecular structures of chemicals, peptides and therapeutic biologicals (including antibodies) used for experimentation. Indeed one of the roles of IUPHAR (as NC-IUPHAR) is to review and recommend protein target nomenclature, in collaboration with the Human Gene Nomenclature Committee (HGNC). The paper featured here is a technical review [1] of identifier qualities and best practices that facilitate large-scale data integration. Read the full article on our blog

(1) McMurray et al. (2017). Identifiers for the 21st century: How to design, provision, and reuse persistent identifiers to maximize utility and impact of life science data. PLoS Biol. 29;15(6). [PMID:28662064].


June 2017

Comparative transcriptomics in human and mouse
(1) Breschi A et al. (2017). Comparative transcriptomics in human and mouse. Nat Rev Genet, 18(7):425-440. [PMID:28479595]


An Expanded View of Complex Traits: From Polygenic to Omnigenic
(1) Boyle EA et al. (2017). An Expanded View of Complex Traits: From Polygenic to Omnigenic. Cell, 169(7):1177-1186. [PMID:28622505]


Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40
(1) Lu J et al. (2017). Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol., doi: 10.1038/nsmb.3417. [Epub ahead of print] [PMID:28581512]


Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A
(1) Paulino C et al. (2017). Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A. Elife, 6: e26232. [PMID:28561733]


Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

Comments by Chris Southan (@cdsouthan)

The historical context for this commentary can be found in this blogpost. This latest report, based on activity-based profiling (ABPP), constitutes the first open biochemical investigation of BIA 10-2474 (1). The ABPP results show it inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. In addition BIA 10-2474 (but not PF04457845) produced substantial alterations in lipid networks in human cortical neurons. The authors are appropriately cautious in not over-extrapolating their findings to causality of pathology recorded in the unfortunate patients (see clinical report in PMID 27806235). However, biochemical and pharmacological questions still remain. One of these is that, given the initial binding interaction is no less than three orders of magnitude lower that PF004457845, it's not entirely clear why 10-2474 was chosen as the lead. Another question is the basic kinetic parameters for purified enzymes (not just crude cell extracts in vitro) are still not available. This should include at least two methods for confirming irreversibility (e.g. IC50 vs pre-incubation or using a 10-2474 radiolabeled derivative). Word has it that a BIAL paper is in preparation so this aspect might be addressed by new results. Note also there are now two compound suppliers in PubChem offering BIA 10-2474 so more experimental reports could be expected. Read the full article on our blog

The GtoPdb entries below have been updated with key interactions from this paper and will go live at the next release.
BIA 10-2474
PF004457845
FAAH
FAAH2

(1) van Esbroeck ACM et al. (2017). Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science, 356(6342): 1084-1087 [PMID:28596366]


Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect?
(1) Welsh P et al. (2017). Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect? Br J Pharmacol., doi: 10.1111/bph.13818. [Epub ahead of print] [PMID:28409825]


GDF15 is a heart‐derived hormone that regulates body growth
(1) Wang T et al. (2017). GDF15 is a heart‐derived hormone that regulates body growth. EMBO Mol Med., doi: 10.15252/emmm.201707604. [Epub ahead of print] [PMID:28572090]


GPR3 and GPR6, novel molecular targets for cannabidiol

Comments by Steve Alexander (@mqzspa)

Cannabidiol is a major metabolite from the Cannabis plant, although levels vary dependent on genetic, regional, cultivation and other factors. It lacks the psychotropic nature of THC, but has been reported to have many biological effects, to the extent that clinical trials for infantile intractable epilepsy are currently ongoing in the US. GPR3 and GPR6 are orphan GPCRs, which have previously been reported to elevate cAMP levels constitutively when expressed in recombinant systems. Although there was some evidence for activation by sphingosine 1-phosphate, this was not reproduced. In this report, a number of endogenous and Cannabis-derived metabolites were examined for their effects on β-arrestin2 recruitment in cells expressing either GPR3 or GPR6. Of these agents, only CBD caused a reduction in β-arrestin2 recruitment in a concentration-dependent manner, with pIC50 values of 5.9 and 6.7 at GPR3 and GPR6, respectively. The authors suggest that the inverse agonist nature of CBD at these receptors might be of relevance for neurodegenerative disorders, such as Parkinson’s and Alzheimer’s Disease. Read the full article on our blog

(1) Laun AS, Song ZH. (2017) GPR3 and GPR6, novel molecular targets for cannabidiol. Biochem Biophys Res Commun. doi: 10.1016/j.bbrc.2017.05.165. [Epub ahead of print] [PMID:28571738]


Crystal structure of the GLP-1 receptor bound to a peptide agonist.
(1) Jazayeri A et al. (2017). Crystal structure of the GLP-1 receptor bound to a peptide agonist. Nature, doi: 10.1038/nature22800. [Epub ahead of print] [PMID:28562585]


Identification of the gene that codes for the σ2 receptor
(1) Alon A et al. (2017). Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci U S A., doi: 10.1073/pnas.1705154114. [Epub ahead of print] [PMID:28559337]


May 2017

Structure of the human multidrug transporter ABCG2.
(1) Taylor NMI et al. (2017). Architecture of the human interactome defines protein communities and disease networks. Nature, 2017 May 29. doi: 10.1038/nature22345. [Epub ahead of print] [PMID:28554189].


Microbiota in T-cell homeostasis and inflammatory diseases
(1) Lee N. & Kim W-U. (2017). Microbiota in T-cell homeostasis and inflammatory diseases. Experimental & Molecular Medicine, 49, e340; doi:10.1038/emm.2017.36. [Full text].


Architecture of the human interactome defines protein communities and disease networks
(1) Huttlin E.L. et al. (2017). Architecture of the human interactome defines protein communities and disease networks. Nature, 545(7655):505-509. [PMID:28514442].


Structural Basis for Apelin Control of the Human Apelin Receptor

Comments by Anthony Davenport, David Huggins, Janet Maguire, and Robert Glen

Activation of the apelin receptor by the peptides apelin or Elabela/Toddler mediates vasodilatation and positive inotropic effects in the adult cardiovascular system and knocking out the receptors results in failure of the heart to develop in developing embryos. To date, only a limited number of Family A structures (including opioid, endothelin ETB, and orexin OX1 and OX2) have been deduced using X-ray crystallography. Ma et al., (2017) have recently reported the 2.6-Å resolution crystal structure of human apelin (APJ) receptor in complex with a synthetic 17-amino-acid apelin analogue agonist. The authors identify a two-site ligand binding mode that has not been seen in previous solved Family A receptor structures. The structure is in reasonable agreement with studies using NMR (Langelaan et al 2013) and molecular dynamics simulations (Macaluso and Glen 2010, Yang et al, 2017) In addition, many of the key interfacial receptor:agonist residues identified from the crystal structure are in agreement with mutation data on apelin binding. Continue reading the full commentary on our blog

(1) Ma Y et al. (2017). Structural Basis for Apelin Control of the Human Apelin Receptor. Structure, 6:858-866.e4. [PMID:28528775].


Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein
(1) Zhang Y et al. (2017). Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature, doi:10.1038/nature22394. [Epub ahead of print]. [Full text].


Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand

Comments by Shane C. Wright, Gunnar Schulte (Karolinska Institutet)

The recently published structure of a full-length SMO bound to the stabilizing compound TC114 builds on emerging concepts from earlier crystal structures of SMO and provides novel insight into how structural rearrangements of the CRD relative to the receptor core coordinate receptor activation while relating this to WNT receptors [1]. Read the full article on our blog

(1) Zhang X et al. (2017). Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. Nat Commun., 8:15383. [PMID:28513578].


Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators

Comments by Patrick Sexton (Monash University, Melbourne)

The glucagon-like peptide-1 receptor (GLP-1R) is a major target for treatment of Type 2 diabetes but has been refractory to the development of small molecule compounds as potential therapeutics. Song et al., (1) report the first crystal structures of the GLP-1R transmembrane domain in complex with 2 distinct negative allosteric modulators (NAMs) (PF-06372222 and NNC0640). Read the full article on our blog

(1) Song G et al. (2017). Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature, doi: 10.1038/nature22378. [Epub ahead of print]. [PMID:28514449].


Structure of the full-length glucagon class B G-protein-coupled receptor

Comments by Laurence J. Miller (Mayo Clinic, Scottsdale, AZ, USA)

Zhang et al. (1) now report a crystal structure of full length glucagon receptor (GCGR) in an inactive conformation stabilized by the non-peptidyl antagonist, NNC0640, and mAb1, bound to the ECD. In this new structure, the ECD is elongated above the TMD, with mAb1 resting on extracellular loop 1 (ECL1), and with the stalk region that links the two dominant receptor domains present in a β-strand conformation lying across the helical bundle between ECL1 and ECL2/ECL3. Read the full article on our blog

(1) Zhang H et al. (2017). Structure of the full-length glucagon class B G-protein-coupled receptor. Nature, doi: 10.1038/nature22363. [Epub ahead of print]. [PMID:28514451].


Selectivity determinants of GPCR–G-protein binding

Comments by Chris Southan (@cdsouthan)

As a detailed comparative sequence/structure/evolution analysis it is relatively unusual (in a good sense) to see such a bioinformatics article in Nature. This tour de force was a collaboration between MRC Laboratory of Molecular Biology, Cambridge UK and the Department of Drug Design and Pharmacology, University of Copenhagen (home of the GPCRdb team). As we know, GPCR signal transduction involves the binding of ligand-activated receptors to their appropriate Gα proteins. In this work selectivity-determining positions for signal transduction (as structural "barcodes") were inferred by comprehensively comparing the sequence conservation between paralogues and orthologues, incorporating information from recent structures. The residue positions for the interaction interfaces are collated and presented at gpcrdb.org (tab ‘Signal Proteins’) for all human receptors and their 16 Gα proteins. This will be updated (including data from new structures) as a guide to interface determinants of coupling selectivity. Many applications of this resource can be envisaged. These could include: exploring options to target GPCR-G protein interfaces with agents that block coupling between the receptor and G protein intracellularly, protein engineering, structural studies and understanding the consequences of natural variation or rare disease associated mutations occurring in the vicinity of the barcode positions.

Note that all GtoPdb GPCRs have cross-references to GPCRdb (who we collaborate with) so users can navigate structural data (including the barcode positions) via GPCRdb, but also exploit ligand-centric navigation via GtoPdb and links out to genomic variants via the Ensembl links. Read the full article on our blog

(1) Flock et al. (2017). Selectivity determinants of GPCR-G-protein binding. Nature545: 317-322. [PMID:28489817].


Protein-phospholipid interplay revealed with crystals of a calcium pump

Comments by Steve Alexander (@mqzspa)

Norimatsu and colleagues [1] have used X-ray solvent contrast modulation to assess density maps of four activation statses of SERCA1. Their observations suggest an unexpected movement of the transporter core, which allows an exaggerated ‘waving’ of the cytoplasmic-extended calcium-binding domain during the cycle of calcium transport. Read the full article on our blog

(1) Norimatsu et al. (2017). Protein-phospholipid interplay revealed with crystals of a calcium pump. Nature, 545(7653):193-198. [PMID:28467821].


Consequences Of Natural Perturbations In The Human Plasma Proteome
(1) Sun et al. (2017). Consequences Of Natural Perturbations In The Human Plasma Proteome. bioRxiv, doi:10.1101/134551. [bioRxiv: 134551].


Assessment of the significance of patent-derived information for the early identification of compound–target interaction hypotheses
(1) Senger, S. (2017). Assessment of the significance of patent-derived information for the early identification of compound–target interaction hypotheses. Journal of Chemoinformatics, 9:26, doi: 10.1186/s13321-017-0214-2. [SpringerOpen: view article].


A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures
(1) Wong et al. (2017). A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures. Immunity, 45(2):442-5. [PMID: 27521270].


April 2017

New developments in cryo-electron microscopy reveal the first Class B GPCR active structure in complex with a G protein

Comments by Dr. Fiona H. Marshall (Director & CSO, Heptares Therapeutics) (@aston_fm)

Solving fully active structures in complex with G proteins is challenging. Recent advances in cryo-electron microscopy (cryo-EM) mean that near atomic resolution is becoming possible for protein complexes of smaller molecular size (sub 100kDa). Using the volta phase plate greatly increases the contrast, particularly at the lower end of the molecular size range, meaning that structures of GPCR complexes are now within reach. The first example of this has been published [1]. Read the full article on our blog

(1) Liang et al. (2017). Phase-plate cryo-EM structure of a class B GPCR–G-protein complex. Nature, doi: 10.1038/nature22327. [PMID: 28437792].


Last rolls of the yoyo: Assessing the human canonical protein count
(1) Southan, C. (2017). Last rolls of the yoyo: Assessing the human canonical protein count. F1000Research, 6:448. [F1000: doi:10.12688/f1000research.11119.1].


Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity
(1) Saleheen et al. (2017). Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature, 544(7649):235-239. [PMID: 28406212].


The Drug Repurposing Hub: a next-generation drug library and information resource
(1) Corsello et al. (2017). The Drug Repurposing Hub: a next-generation drug library and information resource. Nat. Med., 23(4):405-408. [PMID: 28388612].


Neurokinin 3 receptor antagonism for menopausal hot flushes

Comments by Chris Southan (@cdsouthan)

Neurokinin B signalling is increased in menopausal women and has been implicated as an important mediator of hot flushes. A phase 2 trial has assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901 (AZD2624)) [1]. Read the full article on our blog

(1) Prague et al. (2017). Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet, S0140-6736(17)30823-1. [PMID: 28385352].


Fish peptide treats cardiovascular disease

Comments by Chris Southan (@cdsouthan)

The novel GPCR peptide ligand Elabela/Toddler (APELA, Ela), first identified in the fish Danio and critical for the development of the heart, has now been identified in the human cardiovascular system. Yang et al. [1] have recently showed that the peptide binds to the apelin receptor in human heart. Read the full article on our blog

(1) Yang et al. (2017). Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of Its Expression in Pulmonary Arterial Hypertension. Circulation, 135(12):1160-1173. [PMID: 28137936].


Crystal structures of human AT2 reveal molecular mechanism for lack of desensitization and internalization

Comments by Anthony Davenport

The intracellular signal transduction processes activated by the angiotensin AT2 receptor, are atypical for a GPCR and different from the AT1 receptor. Although the classic motifs a GPCR are present in AT2 receptor; it fails to demonstrate classic features of G-protein signalling such as desensitization by phosphorylation, and receptor regulation by internalization. Zhang et al. [1] report the crystal structures of human AT2 bound to an AT2-selective ligand and to an AT1 /AT2 dual ligand, capturing the receptor in an active-like conformation. Read the full article on our blog

(1) Zhang et al. (2017). Structural basis for selectivity and diversity in angiotensin II receptors. Nature, 544(7650):327-332. [PMID: 28379944].


The druggable genome and support for target identification and validation in drug development (3rd Apr 2017)
(1) Finan et al. (2017). The druggable genome and support for target identification and validation in drug development. Science Translational Medicine, 29(383) eaag1166. [Science Trans Med: Full text].


March 2017

FDA allows marketing of tests to provide genetic risk information
The FDA approved genetic testing company 23andMe to sell customers their susceptibility to heritable genetic traits. Many of these are pharmacologically revelevant

FDA news release


Structural insights into adiponectin receptors suggest ceramidase activity

Comments by Steve Alexander (@mqzspa)

Adiponectin receptors, Adipo1 and Adipo2 suggested to exhibit ceramidase activity - based on in silico evidence [1]. Read the full article on our blog

(1) Vasiliauskaité-Brooks et al. (2017). Structural insights into adiponectin receptors suggest ceramidase activity. Nature, 544(7648):120-123. [PMID: 28329765].


Molecular Structure of the Human CFTR Ion Channel
(1) Liu et al. (2017). Molecular Structure of the Human CFTR Ion Channel. Cell, 23;169(1):85-95. [PMID: 28340353].


Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research
(1) Manolio et al. (2017). Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research. Cell, 169(1):6-12. [PMID: 28340351].


Drug Target Ontology to Classify and Integrate Drug Discovery Data
(1) Lin et al. (2017). Drug Target Ontology to Classify and Integrate Drug Discovery Data. bioRxiv, doi:10.1101/117564. [bioRxiv: 117564].


Functional Social network architecture of human immune cells unveiled by quantitative proteomics
(1) Rieckmann et al. (2017). Social network architecture of human immune cells unveiled by quantitative proteomics. Nat. Immunol., 18(5):583-593. [PMID: 28263321].


Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation
(1) Kim et al. (2017). Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation. Cell, 168(6):1053-1064. [PMID: 28283061].


An atlas of human long non-coding RNAs with accurate 5′ ends
(1) Hon et al. (2017). An atlas of human long non-coding RNAs with accurate 5′ ends. Nature, 543(7744):199-204. [PMID: 28241135].


The Ecstacy and Agony of Assay Interference Compounds
(1) Alrich et al. (2017). The Ecstacy and Agony of Assay Interference Compounds. Biochemistry, 56(10):1363-1366. [PMID: 28244742].


Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1

Comments by Prof. Ian Kerr (University of Nottingham) (@iankerr_science)

Despite a flurry of mammalian ATP binding cassette (ABC) transporter structures in the last 2 years the Holy Grail has still been to determine how these diverse proteins interact with their transport substrates. Jue Chen and colleagues at the Rockefeller have now accomplished this for the multidrug resistance protein-1 (MRP1/ABCC1) using advances in high resolution cryo-electron microscopy to show the structures of substrate-free and leukotriene C4 bound protein [1]. Read the full article on our blog

(1) Johnson Z.L., Chen J. (2016). Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1. Cell, 9;168(6):1075-1085.e9. [PMID: 28238471].


The complete structure of an activated open sodium channel
(1) Sula et al. (2017). The complete structure of an activated open sodium channel. Nat. Commun., 8:14205. [PMID: 28205548].


Peripherally administered orexin improves survival of mice with endotoxin shock
(1) Ogawa et al. (2017). Peripherally administered orexin improves survival of mice with endotoxin shock. Elife, 30;5. [PMID: 28035899].


Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling
(1) Alvarez-Curto et al. (2017). Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling. J. Biol. Chem., 291(53):27147-27159. [PMID: 27852822].


Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity
(1) Glukhova et al. (2017). Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity Cell, 168(5):867-877. [PMID: 28235198].


The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes
(1) Simon et al. (2017). The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes. Mol. Pharmacol., 91(5):518-532. [PMID: 28254957].


Pharmacology of Modulators of Alternative Splicing
(1) Bates et al. (2017). Pharmacology of Modulators of Alternative Splicing. Pharmacol. Rev., 69(1):63-79. [PMID: 28034912].


Ligand and Target Discovery by Fragment-Based Screening in Human Cells
(1) Parker et al. (2017). Ligand and Target Discovery by Fragment-Based Screening in Human Cells. Cell, 168(3):527-541. [PMID: 28111073].


Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin
(1) Metcalf et al. (2017). Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med. Chem. Lett., 8(3):321-326. [PMID: 28337324].


Crystal Structure of an LSD-Bound Human Serotonin Receptor
(1) Wacker et al. (2017). Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell, 168(3):377-389. [PMID: 28129538].


Structures of the Human HCN1 Hyperpolarization-Activated Channel
(1) Lee C.H. & MacKinnon R. (2017). Structures of the Human HCN1 Hyperpolarization-Activated Channel. Cell, 168(1-2):111-120. [PMID: 28086084].


Structure of a Pancreatic ATP-Sensitive Potassium Channel
(1) Li et al. (2017). Structure of a Pancreatic ATP-Sensitive Potassium Channel. Cell, 168(1-2):101-110. [PMID: 28086082].


February 2017

A global genetic interaction network maps a wiring diagram of cellular function
(1) Costanzo et al. (2016). A global genetic interaction network maps a wiring diagram of cellular function. Science, 353(6306). [PMID: 27708008].


Orphan receptor ligand discovery by pickpocketing pharmacological neighbors
(1) Ngo et al. (2017). Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat. Chem. Biol., 13(2):235-242. [PMID: 27992882].


Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists
(1) Zheng et al. (2016). Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature, 540(7633):458-461. [PMID: 27926736].


Intracellular allosteric antagonism of the CCR9 receptor
(1) Oswal et al. (2016). Intracellular allosteric antagonism of the CCR9 receptor. Nature, 540(7633):462-465. [PMID: 27926729].


Visualizing GPCR ‘Megaplexes’ Which Enable Sustained Intracellular Signaling
(1) Marshall F. H. (2016). Visualizing GPCR ‘Megaplexes’ Which Enable Sustained Intracellular Signaling. Trends Biochem Sci, 41(12):985-986. [PMID: 27825513].


Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2
Guide to Pharmacology: Ryanodine receptor family
(1) Peng et al. (2016). Novel agonist bioisosteres and common structure-activity relationships for the orphan G protein-coupled receptor GPR139. Sci. Rep., 6, 36681. [PMID: 27830715].


January 2017

The orphan GPR139 receptor is activated by peptides

Comments by David E. Gloriam and Anne Cathrine Nøhr Jensen (Department of Drug Design and Pharmacology, University of Copenhagen)

Two new publications on the orphan class A GPCR, GPR139. The first describing the first combined structure-activity relationships of all surrogate agonists, and a common pharmacophore model for future ligand identification and optimization [1]. The second, showing that the endogenous melanocortin 4 receptor agonists,; adrenocorticotropic hormone and α- and β-melanocyte stimulating hormone in the low micromolar range. In addition, a potentially novel subpeptide (from consensus cleavage site) represents the most potent putative endogenous activator, so far (EC50 value of 600 nM) [2]. Read the full article on our blog

(1) Shehata, M.A. (2016). Novel agonist bioisosteres and common structure-activity relationships for the orphan G protein-coupled receptor GPR139. Sci. Rep., 6, 36681. [PMID: 27830715].

(2) Nøhr, A.C. et al. (2016). The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW. Neurochem Int., 102:105-113. [PMID: 27916541].


X-ray crystallographic study defines binding domains for Ca2+ antagonist drugs and their molecular mechanism of action

Comments by Jörg Striessnig (Department of Pharmacology and Toxicology – Institute of Pharmacy, Universität Innsbruck)

This year witnessed a tremendous progress in our understanding of the structure-function relationship of voltage-gated Ca2+ channels. This is based on the cryo-electron microscopy structure of the rabbit Cav1.1 Ca2+ channel complex at a nominal resolution of 3.6 Å (see Hot Topics Sep 20, 2016) which is now nicely complemented by a study defining the binding domains for Ca2+ antagonist drugs and their molecular mechanism of action at atomic resolution [1]. Read the full article on our blog

(1) Tang et al. (2016). Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature, 537, 117–121. [PMID: 27556947].


2016

Will the real splice variants please stand up?

Comments by Chris Southan, view full comments on our blog (15th Nov 2016)

The number of alternative mRNA splice forms that map to human protein coding loci has increased to the point that nearly all proteins have such associated database records. This gives rise to the paradox that the gene build pipeline from the latest Ensembl GRCh38 reference genome assembly indicates 19,919 protein coding loci (which shrinks to 19,022 with HGNC annotation stringency) but 198,002 transcripts (i.e. nearly 10 transcripts per protein).


X-ray structure of the endothelin ETB receptor

Comments by Anthony Davenport, view full comments on our blog (28th Oct 2016)

Endothelin is a peptide that acts via two G-protein coupled receptors. ETA mainly causes vasoconstriction. In contrast ETB predominantly acts as a beneficial clearing receptor and by the release of endothelium derived relaxing factors, vasodilatation. This paper describes for the first time the crystal structure of the endothelin ETB receptor [1].

(1) Shihoya et al. (2016). Activation mechanism of endothelin ETB receptor by endothelin-1. Nature, 537, 363-368. [PMID: 27595334].


Synthesis and SAR for depsipeptide natural products as selective G protein inhibitors

Comments by Chris Southan, view full comments on our blog (19th Oct 2016)

A team including the Gloriam Group at the University of Copenhagen (also the home of GPCRDB) have a paper out in Nature Chemistry reporting the first total synthesis of YM-254890 and FR900359 [1] .

(1) Xiong et al. (2016). Total synthesis and structure–activity relationship studies of a series of selective G protein inhibitors. Nat. Chem.,  Nov;8(11):1035-1041. [PMID: 27768111].


X-ray structure of P2X3 receptor

Comments by Steve Alexander, view full comments on our blog (19th Oct 2016)

Extracellular ATP is able to activate two families of cell-surface receptors, one of which is the ligand-gated ion channel family of P2X receptors.

(1) Mansoor et al. (2016). X-ray structures define human P2X3 receptor gating cycle and antagonist action. Nature,  538:66-71. doi: 10.1038/nature19367. [PMID: 27626375].


High resolution structure of the voltage-gated skeletal muscle Ca2+ channel complex

Comments by Jörg Striessnig (Department of Pharmacology and Toxicology – Institute of Pharmacy, Universität Innsbruck)
View full comments on our blog (20th Sep 2016)
In a recent article in Nature [1], Wu et al. present the cryo-electron microscopy structure of the rabbit Cav1.1 complex at a nominal resolution of 3.6 Å.

(1) Wu et al. (2016). Structure of the voltage-gated Ca2+ channel Cav1.1 at 3.6 Å resolution. Nature,  537:191-196 [PMID: 27580036].


Allosteric Modulation of Receptor Function and Regulation

Comments by David E. Gloriam (Department of Drug Design and Pharmacology, University of Copenhagen)
View full comments on our blog (6th Sep 2016)
Changeux and Christopoulos have recently described in Cell [1] how common mechanisms link the allosteric sites of activation and response within the four major receptor families of ligand- and voltage-gated ion channels, G-protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases

(1) Changeux, J.-P. and A. Christopoulos (2016). Allosteric Modulation as a Unifying Mechanism for Receptor Function and Regulation. Cell,  166(5): p. 1084-1102 [PMID: 27565340].


Analysis of protein-coding genetic variation in humans

Comments by Chris Southan
View full comments on our blog
Lek et al. [1] in Nature, describes a tour de force large scale reference data set of high-quality protein-coding variation generated via the Exome Aggregation Consortium (ExAC) [2].

(1) Lek et al. (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature,  536, 285–291 [PMID: 27535533].


Discovery of opioid analgesics with reduced side effects

Comments by Anthony Davenport
View full comments on our blog
Manglik et al. [1], writing in Nature, believe they may have found a new form of painkiller that works just as well as morphine but lacks its potentially lethal side effect.

(1) Manglik et al. (2016). Structure-based discovery of opioid analgesics with reduced side effects. Nature,  8;537(7619):185-190 [PMID: 27533032].


Linking chemistry to papers

Comments by Curation Team
View full comments on our blog
The key value of our curation is the extraction of chemistry-activity-target data from papers. Giving this relationship a formal structure in our database records not only provides direct value for users but this is also propagated globally by other databases that link to and/or subsume our content...


NMDAR inhibiton-independent antidepressant actions of ketamine metabolites

Comments by Curation Team

As an allosteric modulator of the NMDA receptor ketamine has been widely clinically utilized (and abused) since its approval in 1970. However, the molecular mechanism of action (mmoa) which was never entirely clear has now been investigated in a new Nature paper (1). The authors show that metabolism of the (R, S)-ketamine racemate to the corresponding pair of 6-hydroxynorketamine (HNK) stereoisomers is essential for its antidepressant effects. They also show that, in mice, this action is largely residing in the (2R, 6R)-HNK form and is independent of NMDAR inhibition but rather involves an AMPA receptor pathway. This work thus raises the prospect of the eventual identification of a new molecular target for ketamine metabolite action. Commentary on the paper has appeared both in that issue of Nature and on the “In the Pipeline” blog. Somewhat unusually, the authors had already filed part of the data some years ago in WO2013056229 assigned to the US Government. This detailed work leads one to speculate how many other racemic mixtures in clinical use will turn out not only to have complex in vivo metabolism but either adventitious polypharmacolgy (and/or off-target liabilities) as a consequence of mmoa “splitting” between active chiral metabolites. In addition to updating the ketamine entry given above, the following new ligands IDs have been added to the GtoPdb development server. These are 9152 for (S) ketamine, 9153 for (R) ketamine and 9154 for (2R, 6R)-HNK (these will all be available in the GtoPdb 2016.3 release (May/June 2016)). The respective PubChem entries, CID 182137, CID 644025 and CID 89504167 can provide cheminformatic links in the interim. The new Nature publication does not map the metabolite interactions with human NMDAR subunits via in vitro binding constants but if these (and for new targets) are eventually published we will add them.

(1) Zanos et al. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites.
Nature 4 May, Epub ahead of print. doi: 10.1038/nature17998. [PMID: 27144355]

PEN identified as ligand of orphan receptor GPR83

Comments by Anthony Davenport

PEN (amino acid sequence AADHDVGSELPPEGVLGALLRV) is a biologically active peptide generated from proSAAS along with other peptides including BigLEN, which was reported to be a ligand for the ophan receptor GPR171 (1).
GPR83 is currently classified as an orphan receptor (2) and mainly localised in the mouse to the CNS. Despite the absence of an identified endogenous ligand, GPR83 is of interest as it has been implicated in behavior, learning, and metabolic regulation.
The same group have now identified PEN as a ligand activating GPR83 (3). In the ‘gold standard’ of ligand binding, N-terminally tyrosinated radioidodinated rat LEN bound with reasonable affinity ( ~8 nM).
NPY was previously reported as a possible ligand for the rat GPR83, also known as GIR (4). The present authors were unable to detect activity at 1 μM. This was in agreement with Southern et al. (5) who were also unable to detected any activity of thirteen NPY peptides and analogues tested at GPR83 linked to beta-arrestin. Comparatively high concentrations of zinc ions (0.1 mM) have also been reported to activate the receptor (6)

(1) Gomes I et al. (2013). GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding.
Proc. Natl. Acad. Sci. 110(40): 16211-6. doi: 10.1073/pnas.1312938110. [PMID: 24043826]

(2) Davenport AP et al. (2013). International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands.
Pharmacol. Rev. 65(3): 967-86. doi: 10.1124/pr.112.007179. [PMID: 23686350]

(3) Gomes I et al. (2016). Identification of GPR83 as the receptor for the neuroendocrine peptide PEN.
Sci. Signal. 9(425): ra43. doi: 10.1126/scisignal.aad0694. [PMID: 27117253]

(4) Sah R et al. (2007). Interaction of NPY compounds with the rat glucocorticoid-induced receptor (GIR) reveals similarity to the NPY-Y2 receptor.
Peptides. 28(2): 302-9. [PMID: 17240481]

(5) Southern C et al. (2013). Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors.
J Biomol. Screen. 18(5): 599-609. doi: 10.1177/1087057113475480. [PMID: 23396314]

(6) Müller A et al. (2013). G-protein coupled receptor 83 (GPR83) signaling determined by constitutive and zinc(II)-induced activity.
PLoS One. 8(1): e53347. doi: 10.1371/journal.pone.0053347. [PMID: 23335960]

A crystal structure of human σ1 receptor

Comments by Steve Alexander

The sigma receptor has been a ‘receptor-in-waiting’ since extensive binding characterisation several decades ago revealed a ‘fourth’ opioid receptor distinct from the conventional GPCR, delta, kappa and mu opioid peptide receptors (and the more recently defined NOP receptor which responds to nociceptin/orphanin FQ). The sigma receptor also has functional impact, in particular in the nervous and cardiovascular systems, although with no clear molecular mechanism/s for its functional influence. The crystal structure published (1) describes a homotrimer, each subunit having a single transmembrane domain. The transmembrane domains appear to be located at the apices of a triangular structure, which is suggested by the authors to have a sufficiently hydrophobic flat perimembrane surface that it might merge with the membrane. Ligand binding is suggested to be in a deep hydrophobic pocket close to the juncture between cytosolic and transmembrane domains.

(1) Schmidt HR, Zheng S, Gurpinar E et al. (2016). Crystal structure of the human σ1 receptor.
Nature 532(7600): 527-530. doi: 10.1038/nature17391. [PMID: 27042935] [PDB: 5HK1, 5HK2]

A crystal structure of a serotonin transporter - one of the most exploited proteins therapeutically

Comments by Steve Alexander

The 5HT, or serotonin, transporter is one of the most therapeutically-exploited drug targets, through blockade by tricyclic and SSRI antidepressant drugs leading to changes in monoamine signalling in the brain. The crystal structures reported here (1) include complexes with two distinct SSRI, which appear to lock the transporter in an outward-facing conformation through binding to the 5HT binding site. An allosteric site is also suggested, which may correlate with observations of allosteric behaviour of some transport inhibitors.

(1) Coleman JA, Green EM & Gouaux E. (2016). X-ray structures and mechanism of the human serotonin transporter
Nature 532(7599): 334-339. doi: 10.1038/nature17629. [PMID: 27049939] [PDB: 5I6X, 5I6Z, 5I71, 5I73, 5I74, 5I75, 5I66]

A major step towards a therapy for acute pancreatitis

Comments by the curation team

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that can lead to systemic multiple organ dysfunction syndrome (MODS) and death. A research team that includes scientists from Edinburgh University in collaboration with GSK (http://www.ed.ac.uk/medicine-vet-medicine/news-events/latest-news/therapy-organ-failure) have recently published a paper (1) in Nature Medicine describing a major advance in the possible treatment. This includes the description of GSK180 as a potent and specific inhibitor of kynurenine-3-monooxygenase (KMO). Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against MODS in a rat model of AP.
This not only marks a "home-grown" entry into GtoPdb but now also consititutes an entry in the pilot version of our immunopharmacology portal (link to blog).

(1) Mole DJ et al. (2016). Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis
Nat. Med. Feb; 22(2): 202-9. doi: 10.1038/nm.4020. [PMID: 26752518]

Fatty acid amide hydrolase (FAAH) inhibitors and the case of BIA 10-2474

Comments by the curation team

The clinical trial disaster of BIA 10-2474, where one of the Phase 1 trial paricipants died on the 17th of Jan 2016, has been commented on widely, both inside and outside the pharmacology community. A selection of these reports provide context and include quotes from members of NC-IUPHAR and GuidetoPHARMACOLOGY curators.

Nature, vol. 529, issue 7586: Scientist in the dark after French clinical trial proves fatal.
Science, 16 Jan 2016: More details emerge on fateful French drug trial.
BPS News, 22 Jan 2016: Improve early access to data from catastrophic clinical trials: A statement on behalf of the British Pharmacological Society.
Forbes, 18 Jan 2016: Scientists speculate on what caused the Bial drug testing tradegy in France.
Chris Southan blog: The unfortuate case of BIA-10-2474

BIA 10-2474 is a fatty acid amide hydrolase (FAAH) inhibitor that was being developed by the Portuguese company Bial (https://www.bial.com/en/r_d.2/pipeline.29/pipeline.a27.html). In humans, other primates and rabbits there are two paralogoues, FAAH and FAAH2. The amino acid sequence similarity is low and the FAAH2 ortholog is absent from rats and mice. The few studies on FAAH2 report different tissue distributions but a similar pharmacology to FAAH, with modest differences in the potency of inhibitors. Inhibition of FAAH allows accumulation of fatty acid amides, including anandamide. This activates cannabinoid receptors, the same targets as one of the active ingredients of the Cannabis plant, Δ9-tetrahydrocannabinol, THC. In the brain and spinal cord it is thought to act as a neuromodulator rather than a 'standard' neurotransmitter and may acumulate at synapses as an endogenous mechanism to reduce activity in particular pathways. The expectation is that FAAH inhibitors allow an amplification of signalling through the cannabinoid system with a range of therapeutic effects including for anxiety and motor disorders and chronic pain. Many inhibitors have been published but none of those trialed so far have shown sufficient efficacy to be progressed (but also had no adverse event indications).

The BIA 10-2474 structure was eventually released in a clinical trial protocol since there was neither a publication nor a clinical trial database entry. We have mapped this to a Bial patent but without detailed activity profiling (if any additional provenance data appears we will add this). The list of clinical inhibitors is now updated in the FAAH target entry but note that the development has of JNJ-42165279 now been halted as a precautionary measure.

Blocking a receptor on inflammatory microglial cells could protect against Alzheimer’s

Comments by the curation team

Olmos-Alonso et al. (1) generated considerable interest in the media last week. The MRC team from the University of Southampton used a transgenic mouse model of Alzheimer's-like pathology to show that inhibition of CSF1R by a tyrosine kinase inhibitor resulted in the blockade of microglial proliferation. The consequent improved memory and behavioural performance as well as prevention of synaptic degeneration, suggests the therapeutic strategy of modifying CSF1R activation could ameliorate Alzheimer's disease.

Links to the Guide to Pharmacology entries for the colony stimulating factor 1 receptor and the GW2580 ligand.

(1) Olmos-Alonso A, Schetters ST, Sri S et al. (2016). Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology
Brain : epub jan 8 [PMID: 26747862]


2015

What’s been hiding under the bridge? - Ogerin, an allosteric modulator of GPR68

Comments by Anthony Davenport

Huang et al. (1) in an article in Nature describe an integrated experimental and computational approach to discover ligands that they used as a probe to reveal some of the physiological functions of GPR68. This G-protein coupled receptor belongs to a proton sensing family detecting acidic pH, but to date there has been no consensus on the sellctivity and reproducibility of small molecule ligands to explore function. The authors present data on a potent GPR86 positive allosteric modulator (PAM) named ogerin, that supressed recall in fear conditioning in mice. The results implicates GPR68 in anxiety and suggests a potential new drug target in this and related CNS disorders. As proof of principle that this strategy may have wider applicability to orphan GPCRs, allosteric agonist and negative allosteric modulators were also identified for GPR68, also a member of the proton sensing family with a widespread distribution in central and peripheral tissues and is fully activated at pH 6.8, but almost silent at pH 7.8.

(1) Huang XP, Karpiak J, Kroeze WK et al. (2015). Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65
Nature 527: 477-83. [PMID: 26550826]

Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models.

Recommended by Michael Spedding

(1) Huang Y, Skwarek-Maruszewska A, Horré K et al. (2015). Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models.
Sci Transl Med. 7: 309ra164. [PMID: 26468326]

2015 Nobel Prize for drug discovery

Comments by Anthony Davenport

The Nobel Prize in Physiology or Medicine 2015 was awarded for the first time to a scientist based in China, the pharmacologist Youyou Tu for her discovery of artemisinin, identified following screening of herbal remedies for the treatment of malaria and isolated from the wormwood plant, Artemisia annua. The prize was shared with William C. Campbell and Satoshi Ōmura for their discovery of avermectin, isolated from bacterial cell cultures, that was developed as ivermectin, a novel drug effective against infections caused by roundworm parasites that lead to River Blindness (onchocerciasis) and lympharic filariasis. Ivermectin binds selectively to glutamate-gated chloride ion channels in invertebrate muscle and nerve cells, causing increased permeability of the cell membrane to chloride ions. This results in hyperpolarization of the cell, leading to paralysis and death of the roundworm. Ivermectin may also disrupt GABA-mediated central nervous system neurosynaptic transmission. Merck currently donates as Mectizan, 140 million ivermectin treatments for River Blindness and 130 million for lymphatic filariasis (co-administered with albendazole, donated by GlaxoSmithKline), annually. For more information see Nobelprize.org.

A structure for the Alzheimer's disease gamma-secretase complex

Comments by the GtoPdb team

A team from MRC Cambrige, UK has published the structure of human γ-secretase (1). The 3.4 Å resolution, cryo-electron microscopy structure (5A63) provides many insights including mechanistic explanations of mutations related to early-onset Alzheimer's disease (AD). The UniProt entry for the catalytic subunit presenilin 1 (P49768, PSEN1) lists 73 amino acid variants and the authors show these cluster at two hotspots located at the centre of a distinct four transmembrane segment bundle.

Our presenilin 1 entry lists those inhibitors that have reached clinical stages. None have proved clinically effective so far but we will add new ones as they advance. It will be of interest and importance if this breakthrough in structure determination of the complex can identify binding sites for these inhibitors and facilitate Notch-sparing optimisation.
Image of PSEN1 inhibitors table

(1) Bai XC, Yan C, Yang G et al. (2015). An atomic structure of human γ-secretase.
Nature. 525: 212-7. [PMID: 26280335]

New approach to the diagnosis of atherosclerosis

Comments by the GtoPdb team

A new paper "Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography" represents a major step forward in the diagnosis of atherosclerosis. The report introduces vascular calcification as a hallmark of atherosclerosis. While macrocalcification confers plaque stability, microcalcification is a key feature of high-risk atheroma and is associated with increased morbidity and mortality. This study demonstrated the binding of the positron-emitting radioactive tracer, 18F sodium fluoride specifically to calcium within plaques. In terms of selectivity, specificity and pharmacodynamic parameters, this binding is similar to ligand-receptor interactions. This is the only currently available clinical imaging platform that can non-invasively detect micro-calcification in active unstable atherosclerosis.

The position of this disease as a leading cause of death worldwide is reflected in out current release, where a database search for "atherosclerosis" retrieves 28 target and ligand entries.

(1) Irkle A, Vesey AT, Lewis DY et al. (2015). Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography.
Nat Commun. 6: 7495. [PMID: 26151378]

A new biased apelin receptor agonist

Comments by the GtoPdb team

A new publication describes the discovery of first apelin receptor agonist biased towards the desirable positive inotropic and vasodilatory actions of the endogenous peptide but with reduced recruitment of β-arrestin, internalization and desensitization of the receptor (1). The entry for MM07 is ligand id 8523, shown below. This now joins the other ligands for the Apelin receptor.
Image of MM07 ligand entry

(1) Brame AL, Maguire JJ, Yang P et al. (2015). Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.
Hypertension. 65: 834-40. [PMID: 25712721]

Confirmed pairing of GPR139 and amino acids L-Tryptophan and L-Phenylalanine

Comments by the GtoPdb team

In 2014 the Gloriam group (that also hosts GPCRdb) published the first endogenous ligand assignment for GPR139 with L-alpha-amino acids (1). An independent confirmation of the essential amino acids L-Tryptophan and L-Phenylalanine has just appeared from Jansen R&D (2). Related Jansen data has also appeared in patent WO2014152917. In accordance with NC-IUPHAR's recommendations specified in (3), GPR139 thus meets the criteria of independent reports of endogenous ligands. If the deorphanisation is ratified at the next NC-IUPHAR meeting along with concomitant nomenclature changes proposed, we will update the comments accordingly. Meanwhile the GPR139 entry has been updated, including with recently reported surrogate small-molecule ligands, and will go live at the next release.

(1) Isberg V, Andersen KB, Bisig C et al. (2014). Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139.
J Chem Inf Model. 54: 1553-7. [PMID: 24826842]

(2) Liu C, Bonaventure P, Lee G et al. (2015). GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine.
Mol Pharmacol. 2015 Sep 8. pii: mol.115.100412. [Epub ahead of print] [PMID: 26349500]

(3) Davenport AP, Alexander SP, Sharman JL et al. (2013). International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands.
Pharmacol Rev. 65: 967-86. [PMID: 23686350]

Modelling Allosteric Modulation

Communicated via the authors from GPCRdb with comments by the GtoPdb team

A paper in Nature's Scientific Reports, "Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants" (1), reports a comprehensive comparison of the ligands in the context of their binding sites.

Relevant ligand compilations, including allosteric sections, are linked from our receptor entries for mGlu2, mGlu3 and mGlu7. The example of the mGlu3 allosteric ligand table is shown below:
Image of mGlu3 allosteric modulators table
More structural information is available in the linked GPCRdb entries we include for each receptor. The sub-type selective ligands as topics in the paper are:

  • FITM
  • Mavoglurant
  • RO5488608
  • MMPIP
  • We have also now added a record for ML337 with the ligand ID 8765 which will go live at our next database release.

(1) Harpsøe K, Isberg V, Tehan BG et al. (2015). Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants.
Sci Rep. 5: 13869. [PMID: 26359761]

A new approach to mapping ligandable lipid-binding proteins complemented by a knowledgebase for lipid enzymology and biology

Comments by Chris Southan

Two papers in May/June 2015 present a significant expansion in lipid metabolism and its associated prospective target landscape. The Cravatt team are pioneers in activity-based protein profiling (ABPP). In their new Cell paper (1) they adapt the approach to lipid based mass-spec labeling probes for lipid-protein binding interactions, rather than enzymatic turnover per-se. The results picked up ~ 1,000 proteins with just arachidonyl probes. These included not only many unknowns (and by implication novel lipid binding proteins of target interest) but also, unexpectedly, some known drug targets (i.e. as secondary targets). They also report a selective ligand MJN228 for a lipid-binding protein (NUCB1) that perturbs endocannabinoid and eicosanoid metabolism (the interactions entered into the database should be live in our July release). This paper was deemed worthy of comment at the popular "In the Pipeline" blog.

As an orthogonal approach to integrating lipidomic data with biological knowledge Swiss-Prot and SIB have just published their major push on lipid enzymology. Consequently, SwissLipids (2) includes over 244, 000 known and theoretical lipids, over 800 proteins, and curated links to over 620 peer-reviewed publications.

(1) Niphakis MJ, Lum KM, Cognetta AB 3rd et al. (2015). A Global Map of Lipid-Binding Proteins and Their Ligandability in Cells.
Cell. 161: 1668-80. [PMID: 26091042]

(2) Aimo L, Liechti R, Hyka-Nouspikel N et al. (2015). The SwissLipids knowledgebase for lipid biology.
Bioinformatics. 2015 May 5. pii: btv285. [Epub ahead of print] [PMID: 25943471]

Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.

Comments by Anthony Davenport

Booe et al. report two crystal structures that reveal how selectivity of the GPCR, calcitonin receptor-like receptor (CLR) for two key peptides in the cardiovascular system, calcitonin gene-related peptide and adrenomedullin, is modulated by RAMP proteins.

(1) Booe JM, Walker CS, Barwell J et al. (2015). Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor.
Mol Cell. 58: 1040-52. [PMID: 25982113] [PDB: 4RWG, 4RWF]

Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1

Recommended by Tom Bonner

(1) Chrencik JE, Roth CB, Terakado M et al. (2015). Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1
Cell. 161: 1633-43. [PMID: 26091040]

Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

Recommended by Eliot Ohlstein

(1) Zhang H, Unal H, Gati C et al. (2015). Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography
Cell. 161: 833-44. [PMID: 25913193] [PDB: 4YAY]

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

Recommended by Rick Neubig

(1) Yarova PL, Stewart AL, Sathish V et al. (2015). Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma
Sci. Transl. Med. 7: 284ra60. [PMID: 25904744]

Crystal structures of the human adiponectin receptors

Comments by Steve Alexander

Adiponectin receptors are 7-transmembrane receptors but fail to couple to G proteins. Sequence analysis suggested an inverted topology compared to classical GPCR (i.e. an intracellular C-terminus). In this paper, 2.9 and 2.4 Å resolution crystal structures of the AdipoR1 and AdipoR2 are described. Both receptors appear to have a large cavity in which a zinc atom is present, in co-ordination with histidine residues. The authors speculate that this might be associated with a lipid hydrolysis function, thereby allowing regulation of intracellular signalling pathways, such as PPARalpha.

(1) Tanabe H, Fujii Y, Okada-Iwabu M et al. (2015). Crystal structures of the human adiponectin receptors.
Nature. 520: 312-6. [PMID: 25855295] [PDB: 3WXW, 3WXV]

Crystal structures of viral chemokines and receptors provide insights into chemokine recognition

Comments by Michael Spedding

Phil Murphy established the IUPHAR chemokine receptor nomenclature in 2000 (1), and chemokines and their receptors perform important roles in host-pathogen defence, with well-established targets in the case of HIV infection, for example. There is a fast developing host versus bacteria/virus evolutionary 'arms race' which markedly affects structure of ligands and receptors, and also this means that interspecies comparisons can be difficult when there is such evolutionary pressure. This is elegantly shown in two crystal structure papers in Science where Qin et al. (2) show the human CXCR4 receptor cross-linked to the viral chemokine vMIP-II. In contrast, Burg et al. (3) show how the human chemokine CX3CL1 interacts with the virally-encoded US28 receptor. The crystal structures can help the design of new antiviral agents, and show that not all receptors are 'endogenous'.

For more information also read the perspective in Science (4).

(1) Murphy PM, Baggiolini M, Charo IFet al. (2000). International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 52: 145-176. [Full text]

(2) Qin L, Kufareva I, Holden LG et al. (2015). Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine.
Science. 347: 1117-22. [Full text] [PDB: 4RWS]

(3) Burg JS, Ingram JR, Venkatakrishnan AJ et al. (2015). Structural basis for chemokine recognition and activation of a viral G protein–coupled receptor.
Science. 347: 1113-17. [Full text]

(4) Standfuss J (2015). Viral chemokine mimicry.
Science. 347: 1071-72. [Full text]

SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1

Comments by Stephen Alexander

The SoLute Carrier (SLC) family of transporters are associated with movement of solutes across membranes driven by ion gradients. The SLC38 family includes 11 transporters, where two groups of cell-surface transporters are defined, equivalent to system A and system N sodium-dependent amino acid transporters. A further group of six transporters in the SLC38 family have no ascribed function, and so are designated as orphans.

This report describes SLC38A9, one of those orphans, which the authors suggest is a lysosomal transporter able to transport 3H-glutamine, and to a lesser extent, 3H-arginine and 3H-asparagine. Of particular interest is the apparent ability of this transporter to enhance the activity of mTORC1, a nexus for the regulation of cellular metabolism, including protein synthesis. The authors suggest that this transporter may, therefore, represent a mechanism for integration of protein turnover, and hence cell growth and proliferation.

(1) Rebsamen M, Pochini L, Stasyk T et al. (2015). SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1.
Nature. 2015 Jan 7. doi: 10.1038/nature14107. [Epub ahead of print] [PMID: 25561175]

Generic GPCR residue numbers – aligning topology maps while minding the gaps

A new version of the generic GPCR residue numbering system is discussed along with information on using GPCRDB web tools to number any receptor sequence or structure.

(1) Isberg V, de Graaf C, Bortolato A, Cherezov V, Katritch V, Marshall FH, Mordalski S, Pin J, Stevens RC, Vriend G, Gloriam DE (2015). Generic GPCR residue numbers - aligning topology maps while minding the gaps.
Trends Pharmacol Sci. 36: 22-31. [PMID: 25541108]

Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant

Recommended by Tom Bonner

(1) Yin J, Mobarec JC, Kolb P, Rosenbaum DM. (2014). Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant
Nature. Dec 22. doi: 10.1038/nature14035 [Epub ahead of print] [PMID: 25533960] [PDB: 4RNB]


2014

X-ray structure of the mGlu5 receptor

Comments by Fiona Marshall

The team from Heptares have published the structure of the transmembrane domain of the mGlu5 receptor in Nature (1). The structure is in complex with the negative allosteric modulator (NAM) mavoglurant which is currently in clinical trials for OCD and depression and has previously been evaluated in Fragile X disorder. The overall structure is similar to the recently published structure of the related mGlu1 receptor (2) however the ligand binds much deeper within the transmembrane domain. The interactions of mavoglurant with the allosteric binding pocket provide evidence of its mechanism of action as a NAM via the stabilisation of a water network which links transmembrane helices (TM) 3, 6 and 7. The structure also explains why small chemical changes to allosteric modulators can result in 'mode switching' between NAMs and PAMs. This new structure will enable structure based design methods to be applied to this receptor and others in the Class C sub family of GPCRs.

The paper also includes a detailed comparison of the structural features of Class C receptors with those of Class A and Class B. Motifs which are conserved within Class C are compared to those with similar functions in the other classes – for example the ionic lock which anchors TM3 and TM6 regulating receptor activation. This is complemented with mutagenesis experiments which further explore the nature of these structural features and their role in receptor activation and signalling.

(1) Doré, A, Okrasa K, Patel J, Serrano-Vega M, Bennett K, Cooke R, Errey J, Jazayeri A, Khan S, Tehan B, Weir M, Wiggin G and Marshall FH. (2014). Structure of a class C GPCR metabotropic glutamate receptor 5 transmembrane domain.
Nature. 2014 Jul 6. doi:10.1038/nature13396. [Full text] [PDB: 4OO9]

(2) Wu H, Wang C, Gregory KJ, Han GW, Cho HP, Xia Y, Niswender CM, Katritch V, Meiler J, Cherezov V, Conn PJ, Stevens RC. (2014). Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator.
Science. 344: 58-64. [PMID: 24603153]

Crystal structure of a human GABAA receptor

Recommended by Chris Southan

(1) Miller PS, Aricescu AR. (2014). Crystal structure of a human GABAA receptor.
Nature. 2014 Jun 8 doi: 10.1038/nature13293. [Epub ahead of print] [PMID: 24909990] [PDB: 4COF]

Crystal structure of GluN1/GluN2B NMDA receptor

Comments by David Wyllie

The crystal structure of a diheteromeric NMDA receptor composed of GluN1 and GluN2B subunits has been solved (1). Overall the tetrameric structure is similar to that reported for a homomeric GluA2 AMPA receptor (2) in that it is assembled as a dimer of dimers with subunits in a 1-2-1-2 orientation with a pseudo-symmetry mismatch between transmembrane and extracellular domains and a swapping of the pair of dimers between the amino terminal and ligand binding domains. In this respect, in the NMDA receptor complex GluN1 subunits can be considered to be similar to the A-C subunit and GluN2B subunits similar to the B-D subunits of the GluA2 AMPA receptor complex. Nevertheless there are intriguing differences between the two receptor structures. For example, the amino and ligand binding domains in the NMDA receptor structure are considerably more compact than that observed in the GluA2 AMPA receptor and there are sites of interaction both within subunit and between subunits which are present in the NMDA receptor structure but which are absent in the AMPA receptor. These sites of interaction are suggested to relate to the fact that NMDA receptors are regulated by a very much greater number of allosteric modulators than their AMPA receptor counterparts and are likely to inform future studies aimed at developing NMDA receptor subtype-selective ligands.

(1) Karakas E, Furukawa H. (2014). Crystal structure of a heterotetrameric NMDA receptor ion channel.
Science. 344: 992-7. [PMID: 24876489] [PDB: 4PE5]

(2) Sobolevsky AI, Rosconi MP, Gouaux E. (2009). X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
Nature. 462: 745-56. [PMID: 19946266] [PDB: 3KGC, 3KG2]

Update: A second GluN1-GluN2B NMDA receptor structure from Xenopus laevis has been published in Nature (3) with commentary (4).

(3) Lee C-H, Lü W, Carlisle Michel J, Goehring A, Du J, Song X, Gouaux E. (2014). NMDA receptor structures reveal subunit arrangement and pore architecture.
Nature. 511: 191-7. [Full text]

(4) Stroebel D, Paoletti P (2014). Neuroscience: A structure to remember.
Nature. 511: 162-3. [Full text]

The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity.

Recommended by Rick Neubig

Click here for database entry: S1P2 receptor

(1) Kempf A, Tews B, Arzt ME, Weinmann O, Obermair FJ, Pernet V, Zagrebelsky M, Delekate A, Iobbi C, Zemmar A, Ristic Z, Gullo M, Spies P, Dodd D, Gygax D, Korte M, Schwab ME. (2014) The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity.
PLoS Biol. 12: e1001763 [PMID: 24453941]

Serial Femtosecond Crystallography of G Protein-Coupled Receptors

Comments by Anthony Harmar

An x-ray free-electron laser (XFEL) producing individual 50-femtosecond-duration x-ray pulses was used to obtain a high-resolution structure of the human 5-HT2B receptor, bound to the agonist ergotamine, at room temperature. Compared with the structure solved by using traditional microcrystallography (2), the room-temperature XFEL structure probably includes features that more accurately represent the receptor structure and dynamics in a cellular environment. For example, a salt bridge between helices V and VI was identified.

(1) Liu W, Wacker D, Gati C, Han GW, James D, Wang D, Nelson G, Weierstall U, Katritch V, Barty A, Zatsepin NA, Li D, Messerschmidt M, Boutet S, Williams GJ, Koglin JE, Seibert MM, Wang C, Shah ST, Basu S, Fromme R, Kupitz C, Rendek KN, Grotjohann I, Fromme P, Kirian RA, Beyerlein KR, White TA, Chapman HN, Caffrey M, Spence JC, Stevens RC, Cherezov V. (2013). Serial femtosecond crystallography of G protein-coupled receptors.
Science. 342: 1521-4. [PMID: 24357322] [PDB: 4NC3]

(2) Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC. (2013). Structural features for functional selectivity at serotonin receptors.
Science. 340: 615-9. [PMID: 23519215] [PDB: 4IB4]


2013

Activation and allosteric modulation of a muscarinic acetylcholine receptor.

Recommended by Tom Bonner

Click here for database entry: M2 receptor

(1) Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK. (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor.
Nature. 2013 Nov 20. doi: 10.1038/nature12735. [Epub ahead of print] [PMID: 24256733]

Structure of the human CCR5 chemokine receptor bound to the marketed HIV drug maraviroc.

Recommended by Tom Bonner

Click here for database entry: CCR5

(1) Tan Q, Zhu Y, Li J, Chen Z, Han GW, Kufareva I, Li T, Ma L, Fenalti G, Li J, Zhang W, Xie X, Yang H, Jiang H, Cherezov V, Liu H, Stevens RC, Zhao Q, Wu B. (2013) Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex.
Science. 341: 1387-90 [PMID: 24030490]

The role of Melanocortin-2 receptor accessory proteins

Comments by Anthony Harmar:

Melanocortin-2 receptor accessory proteins (MRAP AND MRAP2) are small single–transmembrane domain proteins that colocalise with melanocortin receptors in the endoplasmic reticulum and plasma membrane and are thought to play a role in the processing, trafficking and/or function of these receptors (1). Mutations in MRAP have been shown to be the cause of familial glucocorticoid deficiency type 2, a rare autosomal recessive disorder characterised by high plasma ACTH levels but severe cortisol deficiency (1,2). Normally, plasma glucocorticoid concentrations are regulated by ACTH, which stimulates MC2 receptors in the adrenal cortex to promote corticosteroid synthesis. In the absence of MRAP, MC2 receptors cannot translocate from the endoplasmic reticulum to the plasma membrane and ACTH-induced signalling is extinguished. To explore the function of the related protein MRAP2, Asai et al. (2013) characterised mice with a targeted deletion of Mrap2 and observed that they developed severe obesity at a young age (3). They showed that MRAP2 interacts with the MC4 receptor, a protein previously implicated in mammalian obesity, to enhance the responsiveness of the receptor to α-MSH. Mice with tissue-specific knockout of Mrap2 in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons - implicated in mediating the actions of the MC4 receptor on food intake but not on energy expenditure (4)- became similarly obese to global knockout animals. Sequencing MRAP2 in a cohort of humans with severe, early-onset obesity identified four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may contribute to body weight regulation in humans.

This work has several implications for the development of drugs with actions at melanocortin receptors. Firstly, expression of these receptors in transfected cell lines has been problematic, making it difficult to develop robust assays for new ligands. Co-expression of receptors with MRAPs may make this easier. Secondly, although mutations in MRAPs are a very rare cause of obesity, understanding their mechanisms of action may indicate new approaches to drug development. Thirdly, drugs with an allosteric action on complexes between receptors, MRAPs and other accessory proteins (5) may enable cell type specific and or activity-specific activation of receptors, with potential novel therapeutic benefit. Finally, the new work adds another member to a growing list of proteins that can interact with GPCRs to modulate their cellular distribution, pharmacology and/or signaling (6).

(1) Metherell LA, Chapple JP, Cooray S, David A, Becker C, Ruschendorf F et al. (2005). Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2.
Nature genetics. 37: 166-170 [PMID: 15654338]

(2) Modan-Moses D, Ben-Zeev B, Hoffmann C, Falik-Zaccai TC, Bental YA, Pinhas-Hamiel O et al. (2006) Unusual presentation of familial glucocorticoid deficiency with a novel MRAP mutation.
J Clin Endocrinol Metab. 91: 3713-3717 [PMID: 16868047]

(3) Asai M, Ramachandrappa S, Joachim M, Shen Y, Zhang R, Nuthalapati N et al. (2013) Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.
Science. 341: 275-278 [PMID: 23869016]

(4) Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T et al. (2005) Divergence of melanocortin pathways in the control of food intake and energy expenditure.
Cell. 123: 493-505 [PMID: 16269339]

(5) Breit A, Buch TR, Boekhoff I, Solinski HJ, Damm E, Gudermann T. (2011) Alternative G protein coupling and biased agonism: new insights into melanocortin-4 receptor signalling.
Mol Cell Endocrinol. 331: 232-240 [PMID: 20674667]

(6) Ritter SL, Hall RA. (2009) Fine-tuning of GPCR activity by receptor-interacting proteins.
Nat Rev Mol Cell Biol. 10: 819-30 [PMID: 19935667]

X-ray structures of family B GPCRs.

In 2012 Heptares reported that they had solved the X-ray crystal structure of the first family B GPCR. The structure of the corticotropin-releasing factor receptor 1 has now been published online ahead of print in Nature (1), along with a second paper describing the structure of the human glucagon receptor (2).

(1) Hollenstein K, Kean J, Bortolato A et al. (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1.
Nature. 2013 Jul 17. doi:10.1038/nature12357. [Epub ahead of print] [FULL TEXT]

(2) Sui FY, de Graaf C, Han GW et al. (2013) Structure of the human glucagon class B G-protein-coupled receptor.
Nature. 2013 Jul 17. doi:10.1038/nature12393. [Epub ahead of print] [FULL TEXT]

X-ray structure of the mammalian GIRK2–βγ G-protein complex.

Recommended by Rick Neubig

Click here for database entry: Kir3.2

(1) Whorton MR, Mackinnon R. (2013) X-ray structure of the mammalian GIRK2–βγ G-protein complex.
Nature. 2013 Jun 5. doi: 10.1038/nature12241. [Epub ahead of print] [PMID: 23739333]

The cells and circuitry for itch responses in mice.

Recommended by Anthony Harmar

(1) Mishra SK, Hoon MA. (2013) The cells and circuitry for itch responses in mice
Science. 340: 968-71 [PMID: 23704570]

Betatrophin: A Hormone that Controls Pancreatic β Cell Proliferation.

Recommended by Anthony Harmar

The authors identify a hormone, betatrophin, that is primarily expressed in liver and fat. and promotes pancreatic β cell proliferation, expands β cell mass and improves glucose tolerance (1). The hormone, the product of the C19orf80 gene, has previously been named "lipasin" because of its effects in increasing serum triglyceride levee and inhibiting lipoprotein lipase activity (2). Betatrophin is a member of the family of angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins (3).

(1) Yi P, Park JS, Melton DA. (2013) Betatrophin: A Hormone that Controls Pancreatic β Cell Proliferation.
Cell. 153: 747-58 [PMID: 23623304]

(2) Zhang R. (2012) Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels.
Biochem Biophys Res Commun. 424: 786-92 [PMID: 22809513]

(3) Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC, Hobbs HH. (2012) Atypical angiopoietin-like protein that regulates ANGPTL3.
Proc Natl Acad Sci U S A. 109: 19751-6 [PMID: 23150577]

Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis.

Recommended by Tom Bonner

A paper published online ahead of print in Nature Genetics shows that genetic variants in GPR126 are associated with adolescent idiopathic scoliosis (1). Supplementary figure 3 shows GPR126 expression in 20 human tissues with cartilage showing the highest abundance followed by placenta, liver and bone. The paper also quotes papers reporting GPR126-null mice having limb posture abnormalities and growth failure as well as deficits in peripheral nerve development and myelination (2) and being essential for myelination in zebrafish (3).

(1) Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, Qiu X, Sharma S, Takimoto A, Ogura Y, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Londono D, Gordon D, Herring JA, Watanabe K, Chiba K, Kamatani N, Jiang Q, Hiraki Y, Kubo M, Toyama Y, Tsunoda T, Wise CA, Qiu Y, Shukunami C, Matsumoto M, Ikegawa S. (2013) Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis.
Nat Genet. 45: 676-679 [PMID: 23666238]

(2) Monk KR, Oshima K, Jörs S, Heller S, Talbot WS. (2011) Gpr126 is essential for peripheral nerve development and myelination in mammals.
Development. 138: 2673–2680 [PMID: 21613327]

(3) Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS. (2009) A G protein–coupled receptor is essential for Schwann cells to initiate myelination.
Science. 325: 1402–1405 [PMID: 19745155]

Update to the G Protein-Coupled Receptor list: recommendations for new pairings with cognate ligands

IUPHAR review article published in the journal Pharmacological Reviews updating the G Protein-Coupled Receptor list with recommendations for new pairings with cognate ligands. Click here to access the database pages for orphan GPCRs.

Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR, Pin JP, Spedding M, Harmar AJ. (2013)
International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands.
Pharmacol Rev. 65: 967-86. [Abstract] [Full text]

Evidence for testicular orphan nuclear receptor 4 in the etiology of Cushing disease

Recommended by Rick Neubig

A paper published online ahead of print in PNAS describes evidence for the testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) in the etiology of Cushing disease.

(1) Du L, Bergsneider M, Mirsadraei L, Young SH, Jonker JW, Downes M, Yong WH, Evans RM, Heaney AP. (2013) Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.
PNAS. 2013 May 7 doi: 10.1073/pnas.1306182110 [Epub ahead of print] [Abstract]

Structure of the human smoothened receptor bound to an antitumour agent

Recommended by Anthony Harmar

A paper published online ahead of print in Nature describes the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution.

(1) Wang C, Wu H, Katritch V, Han GW, Huang XP, Liu W, Siu FY, Roth BL, Cherezov V, Stevens RC. (2013) Structure of the human smoothened receptor bound to an antitumour agent.
Nature. 2013 May 1. doi: 10.1038/nature12167. [Epub ahead of print] [PMID: 23636324]

Crystal structures of arrestin

Recommended by Tom Bonner

Two papers published online ahead of print in Nature describe the crystal structures of arrestin. Read the commentary in Nature here.

(1) Kim YJ, Hofmann KP, Ernst OP, Scheerer P, Choe HW, Sommer ME. (2013) Crystal structure of pre-activated arrestin p44.
Nature. 497: 142-6 [PMID: 23604253]

(2) Shukla AK, Manglik A, Kruse AC, Xiao K, Reis RI, Tseng WC, Staus DP, Hilger D, Uysal S, Huang LY, Paduch M, Tripathi-Shukla P, Koide A, Koide S, Weis WI, Kossiakoff AA, Kobilka BK, Lefkowitz RJ. (2013) Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.
Nature. 497: 137-41 [PMID: 23604254]

A pharmacological organization of G protein-coupled receptors

Recommended by Anthony Davenport

(1) Lin H, Sassano MF, Roth BL, Shoichet BK. (2013) A pharmacological organization of G protein-coupled receptors.
Nat Methods. 10: 140-6. [PMID: 23291723]

Crystal structures of the 5-HT1B and 5-HT2B G protein-coupled receptors

Recommended by Tom Bonner

Two papers published online ahead of print in Science describe the crystal structures of the serotonin G protein-coupled receptors 5-HT1B and 5-HT2B.

(1) Wang C, Jiang Y, Ma J, Wu H, Wacker D, Katritch V, Han GW, Liu W, Huang XP, Vardy E, McCorvy JD, Gao X, Zhou EX, Melcher K, Zhang C, Bai F, Yang H, Yang L, Jiang H, Roth BL, Cherezov V, Stevens RC, Xu HE. (2013) Structural Basis for Molecular Recognition at Serotonin Receptors.
Science. 2013 Mar 21 [Epub ahead of print] [PMID: 23519210]

(2) Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC. (2013) Structural Features for Functional Selectivity at Serotonin Receptors.
Science. 2013 Mar 21 [Epub ahead of print] [PMID: 23519215]

A screen of 10000 ligands against 82 GPCRs confirms pairings of cognate ligands with orphan receptors and identifies novel surrogate ligands

An article published online ahead of print in the Journal of Biomolecular Screening reports the results of screening ~10,000 ligands against eighty-two G protein-coupled receptors, mainly orphans, using the PathHunter β-arrestin recruitment assays. Pairings of cognate ligands with orphan receptors were confirmed and a number of novel surrogate ligands identified.

Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS, Davenport AP, Brown AJ, Green A, Wigglesworth MJ, Rees S. (2013)
Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors.
J Biomol Screen. doi: 10.1177/1087057113475480 [Epub ahead of print] [PMID: 23396314]

IUPHAR review article published in the journal Pharmacological Reviews on the nomenclature and pharmacology of the Complement Peptide receptors.

Klos A, Wende E, Wareham KJ, Monk PN. (2013)
International Union of Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors.
Pharmacol Rev. 65: 500-543. [Abstract] [Full text]

The second IUPHAR review article to be published in the British Journal of Pharmacology is "New concepts in pharmacological efficacy at 7TM receptors" by Terry Kenakin.

Kenakin T. (2013)
New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2.
Pharmacol Rev. 65: 500-543. [Abstract] [Full text]

Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.

Recommended by Rick Neubig

A recent article published in the journal PNAS shows that the anti-inflammatory lipid lipoxin A4 is an endogenous allosteric enhancer of the CB1 cannabinoid receptor.

Pamplona FA, Ferreira J, Menezes de Lima O Jr, Duarte FS, Bento AF, Forner S, Villarinho JG, Bellochio L, Wotjak CT, Lerner R, Monory K, Lutz B, Canetti C, Matias I, Calixto JB, Marsicano G, Guimarães MZ, Takahashi RN. (2012)
Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor.
Proc Natl Acad Sci U S A. 109: 21134-9. [PMID: 23150578]


2012

Orphan receptor GPR107 identified as the target of the novel neuropeptide neuronostatin.

Comments by Rick Neubig:

This paper uses an interesting approach of profiling a series of cell lines with or without responsiveness to neuronostatin for expression of orphan receptors. All lines that were responsive expressed a set of 4 orphan receptors. si-RNA-mediated Knock down only of GPR107 prevented neuronstatin-stimulated c-fos mRNA expression. Similar loss-of-function studies were done with antisense oligos in vivo. These results suggest that GPR107 is the target of the novel neuropeptide neuronostatin.

(1) Yosten GL, Redlinger LJ, Samson WK. (2012)
Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107.
Am J Physiol Regul Integr Comp Physiol. 303 (9): R941-9. [PMID: 22933024]

2012 Nobel prize for Chemistry awarded for work on G protein-coupled receptors.

Recommended by Anthony Davenport

The 2012 Nobel prize for Chemistry has been awarded to Robert Lefkowitz and Brian Kobilka for their work on G protein-coupled receptors (GPCRs). Congratulations to Professors Lefkowitz and Kobilka! Click here for the scientific background on this award.

Heptares solves first family B GPCR structure.

Recommended by Anthony Davenport

Heptares solves X-ray crystal structure of the first family B GPCR.

Structure of the chemokine receptor CXCR1.

Recommended by Tom Bonner

A paper in Nature describes the structure of the chemokine receptor CXCR1 in phospholipid bilayers. This is important as it is the first structure of an unmodified GPCR and first structure in a lipid bilayer. It is also the first structure to be determined by NMR spectroscopy.

(1) Park SH, Das BB, Casagrande F, Tian Y, Nothnagel HJ, Chu M, Kiefer H, Maier K, De Angelis AA, Marassi FM, Opella SJ. (2012)
Structure of the chemokine receptor CXCR1 in phospholipid bilayers.
Nature. 491: 779-83. [PMID: 23086146]

Update article on IUPHAR-DB published in Nucleic Acids Research.

An update paper describing new content and features of the IUPHAR Database is to be published in the 2013 Nucleic Acids Research Database Issue. The paper is available online with advance access.

Sharman JL, Benson HE, Pawson AJ, Lukito V, Mpamhanga CP, Bombail V, Davenport AP, Peters JA, Spedding M, Harmar AJ, and NC-IUPHAR. (2013)
IUPHAR-DB: updated database content and new features.
Nucl. Acids Res. (Database Issue). 2012 Oct 18. [Epub ahead of print] [Abstract] [Full text]

IUPHAR review article published on the nomenclature, function and pharmacology of Orexin receptors.

Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ. (2012)
International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology.
Pharmacol Rev. 64: 389-420. [Abstract] [Full text]

How to use the IUPHAR Database: step-by-step protocol and examples

The IUPHAR Database team has produced a comprehensive protocol describing how to use the IUPHAR Database for Receptor Binding Techniques published by Springer Protocols, with step-by-step instructions, screenshots, examples and tips to help users make the most of the database.

Mpamhanga CP, Sharman JL, Harmar AJ, and NC-IUPHAR. (2012)
How to Use the IUPHAR Receptor Database to Navigate Pharmacological Data.
Methods Mol Biol. 897: 15-29. In Receptor Binding Techniques edited by Anthony P. Davenport (Springer Protocols). [PMID: 22674159]

IUPHAR review article published on the pharmacology and functions of VIP and PACAP receptors.

The first in a new series of IUPHAR Review articles in British Journal of Pharmacology.

Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI. (2012)
IUPHAR Reviews 1: Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide.
Br J Pharmacol. 166: 4-17. [PMID: 22289055]

Crystal structures of the μ and κ opioid receptors

Comments by Brian M. Cox:

It is now almost 60 years since Beckett and Casy first proposed that morphine and related drugs must act through a specific receptor in brain to induce analgesia (1), and nearly 40 years since three groups independently showed the presence of high affinity binding sites for such drugs in the central nervous system (2, 3, 4). Another milestone in our understanding of the actions of morphine like drugs comes with the publication this month of the crystal structures of two of the four closely related opioid peptide receptors, the κ opioid receptor (5) and the μ opioid receptor (6). Morphine and other opiates used therapeutically act predominantly through the μ receptor while the κ receptor is activated predominantly by some ketocyclazocines, by the hallucinogenic agent salvinorin A, and by the endogenous opioid dynorphin.

The new reports follow closely on reports earlier this year of other GPCRs. The two groups responsible for these latest developments used similar strategies; the receptors were crystallized as complexes with very tightly binding highly receptor-type-selective antagonist ligands; JDTic in the case of the κ receptor and β-FNA for the μ receptor. Thus in each case the receptor is visualized in an inactive conformation. Nevertheless, some interesting features are immediately apparent. Both receptors crystallized as dimers, with more than one potential interface between adjacent receptor monomers as possible dimerization sites. Higher polymerization states and heterodimerization with other GPCRs are possible. These observations provide a structural basis for earlier proposals that opioid receptors might function as dimers or higher polymers (7). Opiate drugs are also known for their rapid reversibility - the immediacy of the reversal of opiate-induced respiratory depression by naloxone can be dramatic. The new studies show that the ligand binding pockets of both the μ and κ receptors are unusually exposed or open relative to other GPCRs. The accessibility of the binding pocket favors rapid dissociation (except in the case of irreversible antagonists such as β-FNA). Since the affinity of many agonist and antagonists at μ or κ receptors is high despite their rapid reversibility, their association rates must also be very high.

Another feature of opioid receptors is the apparent ability of different ligands acting through the same receptor type to direct signaling through different effector pathways. Ligands for opioid receptors are chemically very heterogeneous. The reported structures for the μ and κ receptors point to accessory sites around the common ligand binding pocket for each receptor that provide additional points of receptor interaction for some ligands. Much work needs to be done to understand the basis of agonism at these receptors, but it is tempting to speculate that these additional interaction sites for some ligands might be exploited in the design of agonists preferentially driving signaling through alternative transduction pathways.

(1) Beckett AH and Casy AF. (1954) Synthetic analgesics: stereochemical considerations.
J Pharm Pharmacol. 12: 986-1001. [PMID: 13212680]

(2) Pert CB and Snyder SH. (1973) Opiate receptor: demonstration in nervous tissue.
Science. 179: 1011-1014. [PMID: 4687585]

(3) Simon EJ, Hiller JM, Edelman I. (1973) Stereospecific binding of the potent narcotic analgesic (3H)etorphine to rat brain homogenate.
Proc Natl Acad Sci USA. 70: 1947-1949. [PMID: 4516196]

(4) Terenius L. (1973) Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex.
Acta Pharmacol Toxicol. 32: 317-320. [PMID: 4801733]

(5) Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. (2012) Structure of the human κ-opioid receptor in complex with JDTic.
Nature. doi: 10.1038/nature10939. [Epub ahead of print] [PMID: 22437504]

(6) Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. (2012) Crystal structure of the μ-opioid receptor bound to a morphinan antagonist.
Nature. doi: 10.1038/nature10954. [Epub ahead of print] [PMID: 22437502]

(7) Jordan BA and Devi L. (1999) G-protein-coupled receptor heterodimerization modulates receptor function.
Nature. 399: 697-700. [PMID: 10385123]

Crystal structure of the S1P1 receptor

Comments by Tony Harmar and Jerold Chun:

The structure of the S1P1 receptor fused with T4 lysozyme, in complex with a selective antagonist sphingolipid mimic (ML056), has been reported at 2.8 Å and 3.35 Å resolution by scientists from the Scripps Research Institute and their drug discovery company Receptos (San Diego, CA). This approach that has revealed important structures of other inactive conformations of GPCRs unbound to G proteins. The structure of the ligand-binding pocket of the receptor suggests that there is limited access for ligand from the extracellular surface of the receptor; rather, ligands may gain access to the binding pocket from within the membrane bilayer, as has been proposed for retinal loading into opsin and for the entry of anandamide into cannabinoid receptors. Modeling and site-directed mutagenesis studies led to the mapping of a putative binding pocket for a subclass of agonists that is distinct from the putative binding site for the endogenous ligand. The active metabolite of the S1P1 agonist fingolimod, which actually appears to involve efficacy through functional antagonistic properties on lymphocytes and CNS cells, represents the first oral therapy for multiple sclerosis, and several other compounds are in development that possess S1P1 modulatory activities. Structural data on the critical signaling complex of S1P1 with its biologically relevant heterotrimeric G proteins, as has been reported for the structure of the β2 adrenergic receptor in complex with Gs, await further studies.

(1) Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC. (2012)
Crystal Structure of a Lipid G Protein–Coupled Receptor
Science. 335: 851-5. [PMID: 22344443]

Structures of M2 and M3 muscarinic acetylcholine receptors

Comments by A.J. Harmar:

The structures of the human M2 receptor and the rat M3 receptor, each in a complex with an inverse agonist (3-quinuclidinyl-benzilate and tiotropium, respectively) have been reported (1,2). In each case, the third intracellular loop of the receptor was replaced with T4 lysozyme – an approach that has been used to obtain crystal structures of several other GPCRs. The overall structures of the two receptors are similar, even in some regions (e.g. intracellular and extracellular loops) that display divergent amino acid sequences. In both cases, there is a “large extracellular vestibule as part of an extended hydrophilic channel containing the orthosteric ligand binding site” – a feature that has not been seen in previous GPCR structures. The orthosteric ligand binding sites share many common features with other unrelated acetylcholine binding proteins. Amino acid residues forming the binding pocket are highly conserved between muscarinic receptor subtypes, explaining why receptor subtype specific orthosteric ligands have been difficult to obtain. However, the new structures demonstrate some differences between the binding sites in M2 and M3 receptors that might permit the development of subtype-selective ligands.

There are significant differences in the position of the cytoplasmic end of TM5 and of ICL2 between the two receptors, which may contribute to their different G protein coupling specificities: the position of TM5 was similar in the Gi/o coupled M2, D3 and CXCR4 receptors, whereas the Gq/11-coupled M3 and H1 receptors exhibit a different conformation. A better understanding of G protein coupling specificity will require solution of the structures of more receptor – G protein complexes, as has been achieved for the β2 adrenoceptor – Gs complex (3).

Simulations of the binding of tiotropium to M2 and M3 receptors showed that the ligand pauses at a known allosteric site during association and dissociation from the receptor, leading the authors to suggest that “conceivably, therapeutic molecules could be rationally engineered to act independently as both allosteric and orthosteric ligands”.

(1) Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi T. (2012)
Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist.
Nature. 482: 547-51. [PMID: 22278061]

(2) Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM, Rosemond E, Green HF, Liu T, Chae PS, Dror RO, Shaw DE, Weis WI, Wess J, Kobilka BK. (2012)
Structure and dynamics of the M3 muscarinic acetylcholine receptor.
Nature. 482: 552-6. [PMID: 22358844]

(3) Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK. (2011)
Crystal structure of the β2 adrenergic receptor-Gs protein complex.
Nature. 477: 549-55. [PMID: 21772288]


2011

IUPHAR review article published on the Calcium-Activated Chloride Channels.

Huang F, Wong X, Jan LY. (2012) International Union of Basic and Clinical Pharmacology. LXXXV: Calcium-Activated Chloride Channels.
Pharmacol Rev. 64: 1-15. [PMID: 22090471]

N.B. This family is not currently listed in IUPHAR-DB. See the Guide to Receptors and Channels (GRAC) page on Calcium-Activated Chloride Channels.

The 7-transmembrane receptor LGR5: A GPCR no more?

Comments by Elizabeth R. Lawlor and Richard R. Neubig, University of Michigan, Ann Arbor, Michigan

LGR5 and its close relatives LGR4 and LGR6 were first identified as a family of structurally distinct 7-transmembrane receptors with homology to glycoprotein hormone receptors. Characterized by large N-terminal extracellular domains comprised of 17 leucine-rich repeats, the ligands and downstream signaling of these receptors have remained a mystery. Two recent papers have now identified secreted R-spondin (RSPO) proteins as ligands for LGR5 and its homologues and have demonstrated that RSPO binding of LGR4/5/6 potentiates canonical Wnt-beta catenin signaling (1,2). LGR5 is a marker of stem cells in the base of intestinal crypts and in hair follicles and has been previously shown to be itself a canonical Wnt target gene in these cells. Moreover, significant data support LGR5+ stem cells as cells of origin for colorectal carcinoma and also implicate LGR5 as a mediator of tumor aggression. The combined data from the Liu and Clevers labs now suggest that by acting as an upstream potentiator of Wnt-beta catenin signaling, LGR5 promotes the proliferation and expansion of stem cell populations. Intriguingly, despite their close identity with FSH, LH and TSH, LGR5 and its homologues do not appear to function as GPCRs. The cumulative data from both groups indicate that RSPO-induced activation of LGR4/5/6 does not signal through G-proteins nor induce beta arrestin translocation. Rather, RSPO-binding of the leucine-rich N-terminal domains leads to an increase in the phosphorylation of the Wnt co-receptor LRP6, thereby upregulating activity of the Frizzled-LRP6 receptor complex and potentiating beta catenin activity. Although it is conceivable that other ligands might exist for LGR5 and its homologues, these recent reports indicate that RSPO-binding of LGR5 maintains stem cell proliferation through Wnt-beta catenin signaling in a manner that is independent of G-protein coupled signaling.

(1) Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. (2011)
R-spondins function as ligands of the orphan receptors Lgr4 and Lgr5 to regulate Wnt/{beta}-catenin signaling.
Proc Natl Acad Sci U S A. 108: 11452-7. [PMID: 21693646]

(2) de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es J, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H. (2011)
Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling.
Nature. Published online ahead of print Jul 4 2011. DOI: 10.1038/nature10337. [PMID: 21727895]

IUPHAR review article published on the nomenclature, distribution and pathophysiological functions of Leukotriene receptors.

Bäck M, Dahlén S-E, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE. (2011)
International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions.
Pharmacol Rev. 63:539-584 [Abstract]

IUPHAR review article published updating the classification of Prostanoid receptors.

Woodward DF, Jones RL, Narumiya S. (2011)
International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress.
Pharmacol Rev. 63:471-538 [PMID: 21752876]

IUPHAR review article published on the nomenclature and classification of Hydroxy-carboxylic Acid receptors (GPR81, GPR109A and GPR109B).

Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP. (2011)
International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B).
Pharmacol Rev. 63: 269-90. [PMID: 21454438]

IUPHAR review article published on the nomenclature and classification of Adenosine receptors.

Fredholm BB, Ijzerman AP, Jacobson KA, Linden J, Müller CE. (2011)
International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update.
Pharmacol Rev. 63: 1-34. [PMID: 21303899]

Progesterone puts a swing in the tail.

Comments by David E. Clapham and John A. Peters:

Two recent reports in Nature by Strünker et al. (1) and Lishko et al. (2) have answered a long standing question in reproductive physiology: how does progesterone cause a rapid influx of Ca2+ into human spermatozoa? Using patch-clamp recording from human mature sperm cells (1,2) and optical techniques (1) the Authors provide compelling evidence that progesterone causes the activation and potentiation of a class of calcium selective ion channel that is activated by depolarization and which is expressed exclusively in the testes and sperm, namely the CatSpers (3). CatSpers are assembled as a complex of pore-forming CatSper1-4 subunits in association with CatSperβ, γ and δ auxiliary subunits, all of which are essential for function (4). Intracellular alkalinization of sperm, as occurs in the female reproductive tract, causes the opening of CatSper channels triggering Ca2+ entry and hyperactivation (whip-like flagellar beats) that are necessary for penetration of the egg cumulus and zona pellucida and subsequent fertilization (4). Alkalinization causes a hyperpolarizing shift in the voltage dependency of CatSper opening, an action that the recent reports (1, 2) also find for low nanomolar concentrations of progesterone, which acts in synergy with increased intracellular pH to stimulate CatSper mediated Ca2+ influx. Crucially, all of the evidence points to non-genomic action of progesterone via a cell surface receptor and, furthermore, to one that does not involve second messenger signalling.

The molecular target of progesterone remains uncertain: the possibilities include the CatSper complex itself, or an associated protein. These studies (1, 2) expand the list of ion channels that are subject to non-genomic regulation by steroid hormones. They also identify an interesting species difference in sperm regulation, since mouse CatSper activity is not increased by progesterone (2). Mechanistically, it is intriguing that the voltage-dependency of the opening of human and mouse CatSper differs substantially (2). Identifying the receptor for progesterone that modulates CatSper may potentially reveal a target for a novel male contraceptive agent in man.

(1) Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyland I, Seifert R. (2011)
The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm.
Nature. 471: 382-386. [PMID: 21412338]

(2) Lishko PV, Botchkina IL, Kirichok Y. (2011)
Progesterone activates the principal Ca2+ channel of human sperm.
Nature. 471: 387-391. [PMID: 21412339]

(3) Clapham DE, Garbers DL. (2005)
International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels.
Pharmacol Rev. 57: 451-454. [PMID: 16382101]

Three papers explore the structures of agonist-bound β-adrenoceptors.

(1) Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, Rasmussen SG, Choi HJ, Devree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK. (2011)
Structure and function of an irreversible agonist-β(2) adrenoceptor complex.
Nature. 469: 236-40 [PMID: 21228876]

(2) Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK. (2011)
Structure of a nanobody-stabilized active state of the β(2) adrenoceptor.
Nature. 469: 175-80 [PMID: 21228869]

(3) Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC, Leslie AG, Schertler GF, Tate CG. (2011)
The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.
Nature. 469: 241-4 [PMID: 21228877]

Commentary in:

(4) Sprang SR. (2011)
Cell signalling: Binding the receptor at both ends.
Nature. 469: 172-3 [PMID: 21228868]

(5) Nature news article from 12th January 2011: "Near-action shots of vital proteins".

An update paper on IUPHAR-DB is published in the 2011 Nucleic Acids Research Database Issue.

Sharman JL, Mpamhanga CP, Spedding M, Germain P, Staels B, Dacquet C, Laudet V, Harmar AJ, and NC-IUPHAR. (2011)
IUPHAR-DB: new receptors and tools for easy searching and visualization of pharmacological data.
Nucl. Acids Res. 39 (Database Issue): D534-D538. [Abstract] [Full text]


2010

A population-specific HTR2B stop codon predisposes to severe impulsivity.

Comments by A.J. Harmar:

Bevilacqua and colleagues (1) identified a single nucleotide polymorphism in the gene encoding the 5-HT2B receptor (HTR2B Q20*) that was significantly associated with impulsivity in a Finnish population of violent offenders and matched controls. The polymorphism, which was only found in Finnish populations, introduces a stop codon into the N-terminal extracellular domain of the receptor, leading to reduced expression of the 5-HT2B receptor protein in the brain. 5-HT2B receptor knockout (Htr2b-/-) mice have reduced viability due to cardiovascular defects, but those that survive have a normal lifespan (2). These mice displayed increased impulsive behaviour, according to several measures.

(1) Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T, Zhou Z, Wedenoja J, Maroteaux L, Diaz S, Belmer A, Hodgkinson CA, Dell'osso L, Suvisaari J, Coccaro E, Rose RJ, Peltonen L, Virkkunen M, Goldman D. (2010)
A population-specific HTR2B stop codon predisposes to severe impulsivity.
Nature. 468: 1061-1066. [PMID: 21179162]

(2) Nebigil CG, Choi DS, Dierich A, Hickel P, Le Meur M, Messaddeq N, Launay JM, Maroteaux L. (2000)
Serotonin 2B receptor is required for heart development.
Proc Natl Acad Sci U S A. 97: 9508-9513 [PMID: 10944220]

Crystal structure of the human dopamine D3 receptor in complex with the small molecule D2/D3-specific antagonist eticlopride.

Chien EYT, Liu W, Zhao Q, Katritch V, Won Han G, Hanson MA, Shi L, Hauck Newman A, Javitch JA, Cherezov V, Stevens RC. (2010)
Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist.
Science. 330 (6007): 1091-1095; DOI: 10.1126/science.1197410. [Abstract] [Full text]

IUPHAR review article published on the nomenclature, distribution and function of the Kisspeptin receptor.

Kirby HR, Maguire JJ, Colledge WH, Davenport AP. (2010)
International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function.
Pharmacol Rev. 62 (4): 565-78. [PMID:21079036]

IUPHAR review article published on the nomenclature of Lysophospholipid receptors.

Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH. (2010)
International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature.
Pharmacol Rev. 62 (4): 579-87. [PMID:21079037]

IUPHAR review article published on the nomenclature and pharmacology of Cannabinoid receptors.

Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA. (2010)
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2.
Pharmacol Rev. 62 (4): 588-631. [PMID:21079038]

IUPHAR review article published on the structure, signalling, accessory proteins, receptor dynamics and pharmacology of Frizzled class receptors.

Schulte G. (2010)
International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors.
Pharmacol Rev. 62 (4): 632-67. [PMID:21079039]

Crystal structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.

Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC. (2010)
Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists.
Science. Published ahead of print Oct 7, 2010; DOI: 10.1126/science.1194396. [PMID:20929726]

Time-resolved FRET between GPCR ligands reveals oligomers in native tissues.

Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, Roux T, Bazin H, Bourrier E, Lamarque L, Breton C, Rives ML, Newman A, Javitch J, Trinquet E, Manning M, Pin JP, Mouillac B, Durroux T. (2010)
Time-resolved FRET between GPCR ligands reveals oligomers in native tissues.
Nat Chem Biol. 6 (8): 587-94. [PMID:20622858]

IUPHAR review article published on the physiology, pharmacology and pathophysiological function of TRP channels.

Wu LJ, Sweet TB, Clapham DE. (2010)
International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family.
Pharmacol Rev. 62 (3): 381-404. [PMID:20716668]

Official IUPHAR nomenclature and review article published on the Apelin Receptor

Pitkin SL, Maguire JJ, Bonner TI, Davenport, AP. (2010)
International Union of Basic and Clinical Pharmacology. LXXIV. Apelin Receptor Nomenclature, Distribution, Pharmacology, and Function.
Pharmacol Rev. 62 (3): 331-42. [PMID:20605969]

Official IUPHAR nomenclature and review article published on Melatonin Receptors

Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. (2010)
International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors.
Pharmacol Rev. 62 (3): 343-80. [PMID:20605968]


2009

X-ray structure, symmetry and mechanism of an AMPA-subtype Glutamate Receptor

Comments by J A. Peters, G.L. Collingridge, M. Spedding and R.W. Olsen:

Ligand-gated ion channels (LGICs) exist as pentameric (i.e., nicotinic ACh, 5-HT3, GABAA and glycine), tetrameric (i.e., ionotropic glutamate) and trimeric (i.e., P2X) complexes. Although an almost complete medium resolution (4Å) structure of the nicotinic ACh receptor of Torpedo has been available for several years (1), it was only recently that a 3.1Å resolution crystal structure of a zebrafish P2X receptor was reported by the laboratory of Eric Gouaux (2). The same laboratory has now revealed in Nature (3) an almost complete 3.6Å resolution crystal structure of a representative of the third structural class of LGIC, the rat homotetrameric GluA2 receptor, in the closed state. The study confirms previous structures of the amino terminal domain (ATD) and ligand binding domain (LBD) obtained in isolation that is in each case arranged as a pair of dimers. Agonist/competitive antagonist binding sites are located within and not between subunits; this differs from the pentameric LGICs which have ligand binding sites at subunit interfaces (1). Remarkably, the new GluA2 receptor study reveals that crossover occurs between the ATD and LBD, such that subunit domains within the dimeric pairs swap. In addition, this structure allows a first glance of the ion channel, around which the subunits no longer exist in pairwise arrangement, but become independent and adopt a four-fold symmetry. The regions of the polypeptide linking the ATD to the LBD, and the latter to the transmembrane domains, are also revealed for the first time in this study, and will no doubt prove important for analyzing mechanisms both of agonist-gated channel opening and desensitization, as well as modulation by allosteric ligands. The laboratory of Eric Gouaux had previously reported the structural basis of desensitization (4) and of partial agonism (5) at the same receptors, and these reports were already of great interest for drug design, in this competitive area. This report is certain to initiate a flurry of experimental activity.

(1) Unwin N. (2005).
Refined structure of the nicotinic acetylcholine receptor at 4Å resolution.
J Mol Biol. 346: 967-989. [PMID: 15701510]

(2) Kawate T, Michel JC, Birdsong WT, Gouaux E. (2009).
Crystal structure of the ATP-gated P2X4 ion channel in the closed state.
Nature. 460: 592-598.[PMID: 19641588]

(3) Sobolevsky AI, Rosconi MP, Gouaux E. (2009).
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
Nature. 462: 745-756. [PMID: 19946266]

(4) Jin R, Banke TG, Mayer ML, Traynelis SF, Gouaux E. (2003).
Structural basis for partial agonist action at ionotropic glutamate receptors.
Nat Neurosci. 6: 803-10. [PMID: 12872125]

(5) Sun Y, Olson R, Horning M, Armstrong N, Mayer M, Gouaux E. (2002).
Mechanism of glutamate receptor desensitization.
Nature. 417: 245-53.[PMID: 12015593]

α2A-adrenergic receptor contributes to Type 2 diabetes

Comments by R.R. Neubig:
Renström and colleagues report in Science Express that overexpression of the α2A-adrenergic receptor, which is encoded by a gene within a region of rat chromosome 1 (Niddm1) that influences susceptibility to diabetes, contributes to the reduced insulin secretion and impaired glucose tolerance in diabetic GK rats. The alpha2 adrenergic blocker yohimbine markedly improved insulin secretion and glucose handling in the diabetic rats. A similar effect was also shown in humans, where SNPs upstream of ADRA2A are associated with reduced glucose-stimulated plasma insulin levels and increased receptor mRNA in islets. This study suggests that in a subset of diabetics, alpha2 blockers that act selectively in periphery could represent a novel therapeutic approach.

(1) Rosengren AH, Jokubka R, Tojjar D, Granhall C, Hansson O, Li DQ, Nagaraj V, Reinbothe TM, Tuncel J, Eliasson L, Groop L, Rorsman P, Salehi A, Lyssenko V, Luthman H, Renström E. (2010)
Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes.
Science. 327 (5962): 217-20. [PMID: 19965390]

Official IUPHAR nomenclature and review article published on formyl peptide receptors

Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM. (2009)
International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
Pharmacol Rev. 61 (2): 119-61. [PMID:19498085]

Official IUPHAR nomenclature and review article published on trace amine receptor

Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP. (2009)
International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature.
Pharmacol Rev. 61 (1): 1-8. [PMID:19325074]


2008

Official IUPHAR nomenclature and review article published on free fatty acid receptors

Stoddart LA, Smith NJ, Milligan G. (2008)
International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions.
Pharmacol Rev. 60 (4): 405-17. [PMID:19047536]

Revised recommendations for nomenclature of ligand-gated ion channels

The nomenclature of ligand-gated ion channels and their subunits has recently been re-examined by NC-IUPHAR. Their revised recommendations for nomenclature are summarised here.

Crystal Structure of a human A2A Adenosine Receptor

Comments by S.P.H. Alexander, T.I. Bonner and A. Christopoulos:
Following on from reports of β-adrenoceptor structures reported recently, the 2.6 Å crystal structure of a further Gs-coupled receptor has been reported. The A2A receptor was modified, replacing the third intracellular loop with T4 bacteriophage lysozyme and deleting the C-terminus after the initial 25-30 residues beyond TM7. Purification in the presence of theophylline, which was later exchanged for the more selective A2A receptor antagonist ZM241385 allowed diffraction data to be obtained from the best 13 crystals. From the resulting solved structure, there were three main findings of particular note. The first is the presence of 4 disulfide bonds in the extracellular loop regions, which yields an organization that is very different from previously solved structures of rhodopsin and the β-adrenoceptor structures. Second, the transmembrane helices diverge from the orientations adopted by the corresponding domains in the rhodopsin and adrenoceptor structures. Finally, and perhaps most strikingly, these structural features result in a binding mode of the antagonist that places it in an extended conformation, almost perpendicular to the plane of the membrane, lined up against TM7 and interacting with the loop regions. This pose is very different to that predicted previously based on homology models.

(1) Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC. (2008)
The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist. Science. Nov 21; 322 (5905): 1211-7. [PMID: 18832607]

Structure of the β1-adrenergic receptor

Comments by A.J. Harmar:
Schertler and colleagues report the crystal structure of a β1-adrenergic receptor in complex with the antagonist cyanopindolol. Site directed mutagenesis was used to improve the thermostability of the protein and lock it in the antagonist state. This approach may be a fruitful one for determining the structures of other GPCRs.

(1) Warne T, Serrano-Vega MJ , Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, Schertler GFX. (2008)
Structure of a beta1-adrenergic G-protein-coupled receptor. Nature. Jul 24; 454 (7203): 486-91 [PMID: 18594507]


2007

Crystal structure of human β2-adrenergic receptor

Comments by A.P.Davenport:
To date, only 148 unique structures for membrane proteins have been determined, only 4 of these are human in origin and only one crystal structure of a GPCR has been solved, the visual sensory protein rhodopsin. Three papers in Science and Nature now report the structure of the human β2-adrenergic receptor.

(1) Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK. (2007)
Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature. Nov 15; 450 (7168): 383-7. [PMID: 17952055]

(2) Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. (2007)
High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science. Nov 23; 318 (5854): 1258-65. [PMID: 17962520]

(3) Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK. (2007)
GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science. Nov 23; 318 (5854): 1266-73. [PMID: 17962519]

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