Hot topics in pharmacology archive

2016 | 2015 | 2014 | 2013 | 2012 | 2011 | 2010 | 2009 | 2008 | 2007


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 ( 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 ( 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]


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

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
  • 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]


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]


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]


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]


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]


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]


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]


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]


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]

Back to recent Hot Topics