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X-ray crystal structures of the M1 and M4 muscarinic acetylcholine receptors, revealing differences in the orthosteric and allosteric binding sites that help to explain the subtype selectivity of drugs targeting this family of receptors.

The M₅ muscarinic acetylcholine receptor represents a promising therapeutic target for neurological disorders. Here, the authors reveal a 2.1 Å cryo-EM structure of the M₅ bound to a selective positive allosteric modulator site that enables structure-based drug design.

The A3 adenosine receptor is a promising drug target for cancer, inflammation, and glaucoma. Here, authors determine atomic structures of the human A3 receptor, identifying a previously hidden binding pocket that will aid in the development of more effective A3 receptor-targeted medicines.

Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

The drug Xanomeline is progressing through clinical trials for the treatment of patients with schizophrenia. Here, the authors determine a cryo-EM structure of Xanomeline bound to its primary target revealing a dual binding mode mechanism.

MIPS521, a positive allosteric modulator of the adenosine A₁ receptor, has analgesic properties in a rat model of neuropathic pain through a mechanism by which MIPS521 stabilizes the complex between adenosine, receptor and G protein.

The cryo-electron microscopy structure of the human adenosine A₁ receptor in complex with adenosine and heterotrimeric G_i2 protein provides molecular insights into receptor and G-protein selectivity.

Volta phase-plate cryo-electron microscopy reveals the structure of the full-length calcitonin receptor in complex with its peptide ligand and Gα_sβγ.

The structure of a complex containing calcitonin gene-related peptide, the human calcitonin gene-related peptide receptor and the G_s heterotrimer, determined using Volta phase-plate cryo-electron microscopy, provides structural insight into the regulation of G-protein-coupled receptors by receptor activity modifying protein 1.

Biased agonists act at a receptor to preferentially induce distinct intracellular signalling responses over others. Here the authors show how kinetics of ligand binding and signaling responses greatly influence observed bias profiles, and hence must be considered when studying biased agonists.

Previously, peptide selectivity in the VPAC receptor family of GPCRs was poorly understood. Here, authors combine cryo-EM and MD data to understand binding and selectivity of VPAC1R and PAC1R peptide agonists that can guide future drug development.

GPCRs can form functionally important dimers. Here, authors study impact of dimerization of the secretin receptor on peptide ligand binding and show high receptor conformational dynamics that facilitate G protein recruitment and activation.

Activation signals from GPCRs, the largest receptor family, are transmitted to heterotrimeric G proteins and arrestins, and can be differentially modulated by GPCR phosphorylation. In a recent article, available data, including multiple arrestin structures, are analyzed to decipher common and state-specific conformational changes in arrestins and how these depend on patterns of receptor phosphorylation.

The structure of GLP-1R and its G protein in complex with the small molecule TT-OAD2 sheds light on how the TT-OAD2 agonist can activate the receptor and provides insights into the development of therapeutic agents for metabolic disorders.

A compound previously identified as a dopamine D2 receptor allosteric modulator was found to be a bitopic ligand that binds the orthosteric and allosteric sites to allow binding to one D2 protomer and allosteric modulation of the associated protomer.

The use of atomic-level simulations reveals a molecular mechanism by which a ligand can achieve selectivity between nearly identical receptors, enabling the rational design of targeted drugs.

The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.

The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Here, authors present a cryo-EM structure and biochemical studies of secretin binding to the SecR:Gs complex which show that interactions between peptide and receptor were dynamic.

Use of receptor variants in knock-in mice to dissect phosphorylation-dependent signaling from G protein-dependent signaling mediated by acetylcholine receptor M1 mAChR defines the ability of receptor ligands to modulate anxiety and locomotion behaviors.

Biased ligands of seven-transmembrane receptors (also known as GPCRs), which preferentially activate specific signalling pathways associated with a given seven-transmembrane receptor (GPCR), could have novel therapeutic profiles. Here, the authors discuss which methods may be most appropriate to quantify bias in a drug discovery setting.

Over the past few years, considerable progress has been made in understanding the biology, pharmacology and structure of muscarinic acetylcholine receptors (mAChRs). Here, Wess and colleagues discuss the therapeutic potential of targeting this class of receptors in a range of diseases, including Alzheimer's disease and type 2 diabetes, and consider novel aspects of mAChR pharmacology that could enable modulation of specific receptor subtypes.

Allosteric ligands bind to G protein-coupled receptors at a site distinct from the endogenous ligand. This Review discusses the potential advantages that allosteric ligands could hold, and highlights how the complexity of their actions provides both challenges and opportunities for drug screening.

Very little is known about how a G-protein-coupled receptor (GPCR) transitions from an inactive to an active state, but this study has solved the X-ray crystal structures of the human M2 muscarinic acetylcholine receptor bound to a high-affinity agonist in an active state and to a high-affinity agonist and a small-molecule allosteric modulator in an active state; the structures provide insights into the activation mechanism and allosteric modulation of muscarinic receptors.

G Protein-Coupled Receptors (GPCRs) can adopt different conformations, each linked to distinct cellular outcomes. Here the authors show that compound 17b, a novel agonist of the GPCR family member FPR, robustly activates cardioprotective but not detrimental FPR signalling, showing beneficial therapeutic effect in a mouse model of cardiac infarction.

Binding modes and molecular mechanisms of several allosteric modulators of a prototypical G-protein-coupled receptor are revealed using atomic-level simulations and validated by the rational design of a modulator with substantially altered effects.

G protein–coupled receptors (GPCRs) represent one of the most targeted protein families in pharmaceutical research. Traditionally, drug discovery programmes have searched for ligands that act at endogenous orthosteric sites. Here, Conn and colleagues discuss recent advances in the identification of novel GPCR ligands that act at allosteric sites, highlighting their potential in the treatment of psychiatric and neurological disorders.

The structure of the glucagon-like peptide 1 receptor (GLP-1R) with its biased agonist exendin-P5 sheds light on both receptor activation and the mechanism of biased agonism.

High-resolution structural studies of GPCRs have led to insights into the role of allostery in GPCR-mediated signal transduction.

Allosteric modulation and biased agonism at GPCRs could be manifestations of the same underlying 'conformational selection' mechanism, and these can be harmonized by considering the influence of ligand–receptor residence time and kinetic context.

G protein-coupled receptors (GPCRs) control a plethora of signalling pathways in various contexts. Importantly, a single GPCR can elicit different responses depending on the bound ligand — a phenomenon known as biased agonism. Increasing molecular and structural understanding of biased agonism offers the possibility of designing improved GPCR-targeting drugs.