Search

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

Regional differences in SARS-CoV-2 variants may affect treatment outcome. Here, the authors show that near-sourced convalescent plasma has higher efficacy, as defined by death within 30 days of transfusion, than plasma sourced more than 150 miles away.

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.

Cagrilintide is a long-acting agonist of amylin and calcitonin receptors in late phase trials for obesity. Here, authors present structures of cagilintide with each target receptor, revealing the molecular basis for its non-selective action.

A conjugate drug consisting of GLP-1 receptor agonist and the PPARɑ/ɣ dual-agonist tesaglitazar is shown to have superior anti-diabetic effects than monotherapy.

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.

A mix-and-go system enables the rapid prototyping of antibody formulations, allowing control of their orientation on the surface of LNPs for specific cell targeting, significantly improving the ex vivo and in vivo deliveries of mRNA.

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.

Cryo-EM structure and dynamics analysis provides a conformational mechanism for tuning of selectivity between calcitonin and amylin receptors through targeted lipid modification of residues 19–22 within the ‘bypass’ motif of amylin peptides.

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.

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.

Cryo-EM and molecular dynamics simulation analysis of peptide variants of GLP-1 and exendin-4 reveal distinct receptor conformers with unique modes of peptide–receptor engagement.

The first crystal structures of class B G-protein-coupled receptors have been solved. They reveal features that might inform drug-development strategies for diseases ranging from osteoporosis to diabetes. See Articles p.438 & p.444

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.

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.

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.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

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.

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 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.

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.

Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

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.

There is a need to optimise cryo-EM data acquisition approaches to improve the resolution of GPCR cryo-EM structures to better than 2.5 Å, in order to use them for structure-based drug design purposes. Here, the authors present a systematic analysis of the main cryo-EM experimental parameters using three GPCRs as test cases, which is also of interest for the cryo-EM structure determination of other small membrane proteins.

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 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.

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.

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.

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.

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.

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.

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.

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.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

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) are ubiquitous gatekeepers of cellular response and signal predominantly by recruitment and activation of G proteins. In a recent paper in Nature, Flock et al. use large-scale bioinformatics to build a model of GPCR-G protein selectivity and an interactive database to interrogate potential receptor-G protein interactions.