Blog Archives

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

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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

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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

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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,

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Hot Topics: Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1

Despite a flurry of mammalian ATP binding cassette (ABC) transporter structures in the last 2 years the Holy Grail has still been to determine how these diverse proteins interact with their transport substrates. Jue Chen and colleagues at the Rockefeller

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Hot topics: The orphan GPR139 receptor is activated by peptides

GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression in the striatum and hypothalamus, regions regulating locomotion and metabolism, respectively, and it has therefore been suggested as a

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

This year witnessed a tremendous progress in our understanding of the structure-function relationship of voltage-gated Ca2+ channels. This is based on the cryo-electron microscopy structure of the rabbit Cav1.1 Ca2+ channel complex at a nominal resolution of 3.6 Å ([1]

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Hot topics: Will the real splice variants please stand up?

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

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Hot topics: X-ray structure of the endothelin ETB receptor

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 [1,2]. This paper  describes for

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

A team including the Gloriam Group at the University of Copenhagen (also the home of GPCRDB) have paper out in Nature Chemistry reporting the first total synthesis of YM-254890 and FR900359 [1] . These are related cyclic depsipeptide natural products that

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Hot topics: X-ray structure of P2X3 receptor

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. This family of cation channels is distinct from the remainder of the ligand-gated ion channels, as they

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

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.

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Hot topics: Allosteric Modulation of Receptor Function and Regulation

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. As

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Hot topics: Analysis of protein-coding genetic variation in humans

Leck et al. in Nature, describes a tour de force largest scale reference data set of high-quality protein-coding variation generated via the Exome Aggregation Consortium (ExAC)

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Hot Topics: Discovery of opioid analgesics with reduced side effects

Manglik et al., 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.

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Hot Topics: Linking chemistry to papers

The key value of our curation is the extraction of chemistry-activity-target data from papers.

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