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…

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…

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…

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…

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…

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…

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…

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…

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…

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…

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…

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…

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…

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…