The Cannabis plant is a natural product from which more than 100 apparently unique metabolites (cannabinoids) have been identified. Many of these have been found in human plasma following consumption of Cannabis preparations. The most well-recognised is tetrahydrocannabinol, THC, because…
Blog Archives
GtoPdb: Database Status Reports
As some of our contacts may know, we hold hemi-annual meetings between IUPHAR, BPS the GtoPdb team, together with invited guests from our collaborators and NC-IUPHAR committee representatives. Covering ~ 2.5 days these usually take place in Paris or Edinburgh.…
Hot topic (update): from double to triple whammy for BACE1 inhibitors
19 June 2018 update. Announced only about a week after the events described below, yet a third clinical candidate, lanabecestat (AZD-3293, LY3314814) has also bitten the dust (4). The two PhIII trials were stopped because they were deemed unlikely to meet their…
Posted in Hot Topics
Database release 2018.2
Our second database release of the year, 2018.2, is now available. This update contains the following new features and content changes: Content updates GPCRs: 5-Hydroxytryptamine receptors Adenosine receptors Adrenoceptors Histamine receptors Opioid receptors Lysophospholipid (S1P) receptors Prostanoid receptors NHRs: Mineralocorticoid…
Tagged with: database, GPCRs, ion channels, out-links
Posted in Database updates, Guide to Malaria Pharmacology
Posted in Database updates, Guide to Malaria Pharmacology
Hot topic: Cryo-EM structure of the adenosine A2A receptor coupled to an engineered heterotrimeric G protein
The A2A adenosine receptor is densely expressed in dopamine-rich areas of the brain and in the vasculature. It is the target of an adjunct medication for Parkinson’s Disease, istradefylline in Japan, an A2A receptor antagonist. The A2A adenosine receptor is an example…
Posted in Hot Topics
Hot topic: Conformational plasticity in the selectivity filter of the TRPV2 ion channel
The TRPV2 ion channel is the less well-characterised relative of the TRPV1 or vanilloid receptor that is activated by capsaicin. TRPV2 channels have many similarities to the TRPV1 channels, in that they are homotetrameric and respond to some of the same…
Posted in Hot Topics
Hot topic: 3D structure of the P2X3 receptor bound to a negative allosteric modifier, identifies a binding site that is a target for development of novel therapeutic agents
Negative allosteric modulators (NAMs) are of great interest in drug development because they offer improved scope for the production of receptor antagonists with enhanced subtype-selectivity. Indeed, many NAMs are already on the market or undergoing clinical trials. NAMs act by…
Posted in Hot Topics
Hot topic: 3D structures of the closed acid-sensing ion channel (ASIC) shed light on the activation mechanism of these neuronal ion channels
ASICs are potential drug targets of interest. Their activation mechanism has however remained elusive. ASICs are neuronal, proton-gated, sodium-permeable channels that are expressed in the central and peripheral nervous system of vertebrates. They form a subfamily of the Epithelial Na…
Hot topic: Engineered mini G proteins provide a useful tool for studying the activation of GPCRs in living cells
In order to stabilize the GPCR-G protein complex, an agonist must be bound to the receptor and the alpha subunit of the heterotrimer must be in a nucleotide-free state. Ground-breaking work by expert crystallographers made use of so-called mini G…
Hot Topic: Unexplored therapeutic opportunities in the human genome
Contemporary drug discovery is dominated by two related themes. The first of these is target validation upon which the sustainability of pharmaceutical R&D (in both the commercial and academic sectors) crucially depends. The second is the size of the pool of human…
GtoImmuPdb: technical update March 2018 – beta-release v3
We are pleased to announce the third, beta-release of the Wellcome Trust-funded IUPHAR Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb). Since our last release in August 2017 we have implemented developments that include disease summary pages, graphical browsing features and extensions and improvements…
Posted in Guide to Immunopharmacology, Technical
Database release 2018.1
The first GtoPdb and GtoImmuPdb beta release of 2018 includes plenty of target and ligand updates as well as announcing some important new features. As always, full content statistics for release 2018.1 can be found on the database about page.…
Hot topic: The G Protein-Coupled Receptors deorphanization landscape.
Within the vast GPCR superfamily, orphans are described as receptors devoid of known endogenous ligands. They have been labeled as 7 transmembrane proteins by sequence homology and dispatched accordingly in the different GPCR subfamilies. They have attracted much attention given…
Hot topic: Pharmacogenomics of GPCR Drug Targets
A system of rigorous clinical trials and regulation exist to ensure that a new drug is safe and effective when reaching the market. However, natural human genetic variation(s) may cause individuals to respond differently to the same medication. A collaboration…
PubMed Commons and Altmetrics
This has been split from an updated older post on Citation profiles for our NAR and Concise Guide papers and this section will be updated soon PubMed Commons In addition to keeping an eye on citations per se we also…
Posted in Uncategorized
Hot topic: Trends in GPCR drug discovery: new agents, targets and indications
New avenues for GPCR drug discovery have emerged owing to recent advances in receptor pharmacology, technological breakthroughs in structural biology and innovations in biotechnology. A collaboration between the Department of Drug Design and Pharmacology, University of Copenhagen (home of the…
Impact statements and content subsumation: BPS 2017 follow-up
We were pleased to catch up with many GtoPdb/GtoImmuPdb users, aficionados, friends and affiliates at the BPS Pharmacology 2017 in the QEII Center in London. You can find our presentations and posters on Slideshare. Associated with this presence we have…
Posted in Uncategorized
Database release 2017.6
The sixth and final IUPHAR/BPS Guide to PHARMACOLOGY release of 2017 has been published on 29th November. This release includes new content for the Guide to IMMUNOPHARMACOLOGY, which is currently still in beta phase. This release includes the following updates…
GtoPdb at Pharmacology 2017
The GtoPdb team will be at the British Pharmacological Society’s flagship meeting, Pharmacology 2017, in London, December 11-13th 2017. We are pleased to have our own stand at this meeting and will be present during the refreshment breaks and poster…
GtoImmuPdb: technical update November 2017
This blog-post will discuss the major developments planned for the Guide to IMMUNOPHARMACOLOGY as we look ahead to our next beta-release (v3.0) in early 2018. This month, the updated IUPHAR/BPS Guide to PHARMACOLOGY NAR Database Issue has been published online…
Posted in Guide to Immunopharmacology, Technical
Hot topic: Cryo-EM structures of Mucolipin TRP Channels in the Lysosome: Five Together at Once
The mucolipin subfamily of Transient Receptor Potential (TRP) channels, which consist of TRPML1, TRPML2, and TRPML3 (a.k.a. MCOLN1- 3), are Ca2+-permeable cation channels localized in intracellular endosomes and lysosomes. In response to cellular stimulation, TRPMLs mediate Ca2+ release from the…
The Concise Guide to PHARMACOLOGY 2017/18
Concise Guide to Pharmacology Simplifies Drug Discovery Research The Concise Guide to PHARMACOLOGY 2017/18 (CGTP), which is produced from a subset of the data contained in the IUPHAR/BPS Guide to PHARMACOLOGY database, is now available in the British Journal of…
Tagged with: Concise Guide, ligands, pharmacology, Publications, Target nomenclature
Posted in Concise Guide to Pharmacology, Publications
Posted in Concise Guide to Pharmacology, Publications
GtoPdb NAR database issue 2018: Journal to database connectivity and journal to GtoPdb links
The following blog post acts as supplementary data to the 2018 NAR Database Issue Journal to Database connectivity The citation provenance of all entity records and contextual comments selected by the curators and NC-IUPHAR members in GtoPdb is supported by…
Posted in Chemical curation
GtoPdb NAR database issue 2018: PubChem Content
The following blog post acts as supplementary data to the 2018 NAR Database Issue GtoPdb PubChem Content The GtoPdb PubChem integration strategy has been previously outlined (1). Since 2015 we have made nine PubChem submissions for new releases of our…
Posted in Chemical curation, Publications
Hot topic: A new research avenue investigating mitochondrial GPCR biology
As one of the first propositions for GPCRs being present in mitochondrial membranes, a recent report from Robert Friedlander and colleagues [1] follows on from previous work characterising synaptic and extrasynaptic mitochondria in human cortex (post-mortem samples) and their role…
Hot topic: Crystal structure of LPA6, a receptor for lysophosphatidic acid, at 3.2A
Lysophospholipids (LPs) have myriad roles as extracellular signals that activate cognate G protein-coupled receptors (GPCRs) (2). LPs for which receptors have been reported include lysophosphatidic acid (LPA) (receptors: LPA1-6), sphingosine 1-phosphate (S1P1-5), lysophosphatidyl serine (LPS1-3, 2L (2L is a pseudogene…
Hot topic: FZD6 dimers dissociate after stimulation – briefly
GPCRs of all classes are widely thought to form homodimers, heterodimers and higher-order oligomers. The functional significance of dimerization is well understood for Class C receptors but less certain for the other GPCR classes, including the rather unconventional class F…
Hot topics: A cryptic binding pocket in K2P2 exposes new avenues for drug development.
The TREK subfamily of K2P channels (K2P2, K2P4 and K2P10) pass background potassium currents that modulate the excitability of neuronal cells and cardiac myocytes. In recent years, these channels have received significant attention as potential drug targets. This is in…
Posted in Hot Topics
Anti-infective pilot entries
GtoPdb has been traditionally focused on the pharmacology associated with human diseases (i.e. we have not been funded to cover anti-infectives). In 2017 we have been exploring possible funding opportunities to extend into expert curation of anti-infectives, particularly in the…
Posted in Uncategorized
New source cross-references in release 2017.5
(minor updates 15 Sep 2017) The statistics of content are presented as usual in the release notes and The Guide to IMMUNOPHARMACOLOGY has a separate update. This post describes changes and updates to other resources we provide links to, that…
Database release 2017.5
The 5th IUPHAR/BPS Guide to PHARMACOLOGY database release of 2017 includes updates to several target families, and new targets and ligands added, focusing on those relevant to immunopharmacology. We also announce a new organisation for ligand families and groups. This…
Guide to IMMUNOPHARMACOLOGY – beta release v2.0, August 2017
We are please to announce the second, beta-release of the Wellcome Trust-funded IUPHAR Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb). Since our first beta-release back in May 2016, we have undertaken a user-testing exercise to gather feedback on the layout, navigation and content…
Posted in Guide to Immunopharmacology, Technical
Hot topics: Agonist-bound crystal structures of the CB1 cannabinoid receptor
Antagonist bound crystal structures of GPCRs are useful in giving an insight into the molecular conformation of a receptor’s inactive state whilst enabling the design of new drugs. However, they prove insufficient to understand the activation mechanism of the receptor…
Hot topics: Identifiers for the 21st century
While identifiers are not a traditional “hot topic” in pharmacology the subject is becoming increasingly important. One of the reasons is that for mechanistic pharmacology the community needs to define (and communicate) identifiers for the key entities of model organism…
Hot topics: X-ray crystal of the apelin receptor
Activation of the apelin receptor by the peptides apelin or Elabela/Toddler mediates vasodilatation and positive inotropic effects in the adult cardiovascular system and knocking out the receptors results in failure of the heart to develop in developing embryos. To date,…
HGNC gene links to GtoPdb
As regular users of GtoPdb will be aware, our target pages include HUGO Gene Nomenclature Committee (HGNC) gene symbols, nomenclature and links to HGNC gene pages (Fig 1). HGNC pages in turn link back to GtoPdb target pages under the…
Hot topic: Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474
The historical context for this commentary can be found in this blogpost. This latest report, based on activity-based profiling (ABPP), constitutes the first open biochemical investigation of BIA 10-2474 (1). The ABPP results show it inhibits several lipases that are…
Posted in Hot Topics
Hot topic: GPR3 and GPR6, novel molecular targets for cannabidiol
Cannabidiol is a major metabolite from the Cannabis plant, although levels vary dependent on genetic, regional, cultivation and other factors. It lacks the psychotropic nature of THC, but has been reported to have many biological effects, to the extent that…
Hot topic: Selectivity determinants of GPCR–G-protein binding
As a detailed comparative sequence/structure/evolution analysis it is relatively unusual (in a good sense) to see such a bioinformatics article in Nature. This tour de force was a collaboration between MRC Laboratory of Molecular Biology, Cambridge UK and the Department…
Hot topics: Crystal structure of full-length glucagon receptor provides insight into relative orientation of extracellular and transmembrane domains in an inactive conformation and importance of dynamic changes in this orientation for activation
It has been quite challenging to gain high resolution structural insights into an intact class B G protein-coupled receptor, despite previous solution of multiple structures for the two dominant domains, the extracellular domain (ECD) and the transmembrane helical bundle domain…
Hot topics: Crystal structure of GLP-1 receptor transmembrane domain provides insight into allosteric modulation.
The glucagon-like peptide-1 receptor (GLP-1R) is a major target for treatment of Type 2 diabetes but has been refractory to the development of small molecule compounds as potential therapeutics. Song et al., (1) report the first crystal structures of the GLP-1R…
Posted in Hot Topics
Guide to IMMUNOPHARMACOLOGY – beta release v1.0, May 2017
We are pleased to announce the first, public, beta-release of the Guide to IMMUNOPHARMACOLOGY (GtoImmuPdb). The GtoImmuPdb is a Wellcome Trust-funded extension to the existing Guide to PHARMACOLOGY (GtoPdb) and the beta-release (v1.0) marks an important milestone in its production and development. GtoImmuPdb aims to provide improved data exchange between immunology and pharmacology expert communities, […]
Posted in Guide to Immunopharmacology
Database release 2017.4
Our 4th database release of 2017 was published on 23rd May 2017. It now includes 15133 interactions between 2813 targets and 8900 ligands. For full release statistics see the Guide to PHARMACOLOGY About page. Target Updates Updates have been made to…
Hot topics: New crystal structure of the full-length Smoothened reveals ligand-dependent interaction between extracellular CRD and the 7TM core of the receptor
Molecular details of receptor activation remain scarce when it comes to Class Frizzled receptors and even less is known about the dynamics between the N-terminal cysteine rich domain (CRD) and the transmembrane domain (TMD) in the absence and presence of…
Posted in Hot Topics
Hot Topics: Protein-phospholipid interplay revealed with crystals of a calcium pump
Ca2+-ATPases are members of the P-type transporters and are usually regarded as post-stimulus recovery mechanisms, allowing calcium ions to be removed from the cytosol either via re-accumulation into sarcoplasmic/endoplasmic reticulum (the SERCA pumps) or extrusion outside the cell (the PMCA…
Posted in Hot Topics
Hot Topics: New developments in cryo-electron microscopy reveal the first Class B GPCR active structure in complex with a G protein
The last 10 years has seen a huge increase in the numbers of X-ray structures solved for GPCRs. However solving fully active structures in complex with G proteins remains challenging. Recent advances in cryo-electron microscopy (cryo-EM), including improved direct electron…
Posted in Hot Topics
Hot Topics: Fish peptide treats cardiovascular disease
The novel GPCR peptide ligand Elabela/Toddler (APELA, Ela), first identified in the fish Danio and critical for the development of the heart, has now been identified in the human cardiovascular system. Yang et al. [1] have recently showed that the…
Posted in Hot Topics
Hot Topics: Neurokinin 3 receptor antagonism for menopausal hot flushes
Neurokinin B signalling is increased in menopausal women and has been implicated as an important mediator of hot flushes. A phase 2 trial has assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901). Results showed it safely and…
Posted in Hot Topics
Hot Topics: Crystal structures of human AT2 reveal molecular mechanism for lack of desensitization and internalization
The intracellular signal transduction processes activated by the angiotensin AT2 receptor, are atypical for a GPCR and different from the AT1 receptor. Although the classic motifs a GPCR are present in AT2 receptor; it fails to demonstrate classic features of…
Posted in Hot Topics
Hot Topics: Structural insights into adiponectin receptors suggest ceramidase activity
Adiponectin receptors, divided into Adipo1 and Adipo2, were initially classed as GPCR on the basis of hydropathy analysis suggesting seven transmembrane domains. However, they appear to be present in the cell membrane in a topology inverted compared to the 7TM…
Posted in Hot Topics
