Hot topics in pharmacology

Recent publications of interest recommended by NC-IUPHAR

NMDAR inhibiton-independent antidepressant actions of ketamine metabolites

Comments by Curation Team

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

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

PEN identified as ligand of orphan receptor GPR83

Comments by Anthony Davenport

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

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

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

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

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

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

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

A crystal structure of human σ1 receptor

Comments by Steve Alexander

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

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

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

Comments by Steve Alexander

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

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

A major step towards a therapy for acute pancreatitis

Comments by the curation team

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

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

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

Comments by the curation team

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

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

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

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

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

Comments by the curation team

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

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

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

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

Comments by Anthony Davenport

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

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

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

Recommended by Michael Spedding

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

2015 Nobel Prize for drug discovery

Comments by Anthony Davenport

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

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

Comments by the GtoPdb team

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

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

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

New approach to the diagnosis of atherosclerosis

Comments by the GtoPdb team

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

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

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

A new biased apelin receptor agonist

Comments by the GtoPdb team

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

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

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

Comments by the GtoPdb team

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

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

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

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

Modelling Allosteric Modulation

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

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

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

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

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

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

Comments by Chris Southan

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

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

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

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

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

Comments by Anthony Davenport

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

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

Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1

Recommended by Tom Bonner

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

Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

Recommended by Eliot Ohlstein

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

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

Recommended by Rick Neubig

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

Crystal structures of the human adiponectin receptors

Comments by Steve Alexander

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

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

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

Comments by Michael Spedding

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

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

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

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

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

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

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

Comments by Stephen Alexander

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

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

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

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

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

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

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

Recommended by Tom Bonner

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

Archive of previous years