Hot topics in pharmacology

Recent publications of interest recommended by NC-IUPHAR

2017: Jan | Feb | Mar | Apr | May | June | July | Aug | Sept

September 2017

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., pii: 201705768. doi: 10.1073/pnas.1705768114. [Epub ahead of print] [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., DOI: 10.1073/pnas.1710850114 [Epub ahead of print]. [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].


Archive of previous years