Receptor Mechanisms and Signaling

Discovery of Novel and Selective GPR17 Antagonists as Pharmacological Tools for Developing New Therapeutic Strategies in Diabetes and Obesity

The paper identifies two novel GPR17 antagonists through high-throughput screening that selectively inhibit GPR17 signaling and enhance GLP-1 secretion, offering potential for diabetes and obesity treatment.

The conformational equilibria of a human GPCR compared between lipid vesicles and aqueous solutions by integrative 19F-NMR

This study compares the conformational equilibria of the human A2A adenosine receptor in lipid vesicles and aqueous solutions using 19F-NMR, revealing environment-dependent differences in agonist-bound states.

Arrestin recognizes GPCRs independently of the receptor state

This study shows arrestin2 binds to the β1-adrenergic receptor independently of receptor conformation or ligand type, driven by a conformational change in arrestin induced by a phosphopeptide.

Gz Enhanced Signal Transduction assaY (GZESTY) for GPCR deorphanization

GZESTY is a cell-based assay for Gi/o/z-coupled GPCRs that detects ligand activation and identifies endogenous ligands for orphan GPCRs.

GRKs phosphorylate GPCR C-terminal peptides in a hierarchical manner

This study uses NMR to show GRK1 and GRK2 produce distinct phosphorylation patterns on C-terminal peptides of GPCRs, revealing time-dependent phosphorylation barcodes that may influence arrestin interactions during desensitization.

Profiling of HCAR1 signaling reveals Gαi/o and Gαs activation without β-arrestin recruitment and the discovery of an allosteric agonist

This study identifies and characterizes synthetic ligands for HCAR1 using ebBRET, revealing its activation of Gi/o and Gs pathways without β-arrestin recruitment.

A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism

This study uses APEX2 proteomics to map the spatiotemporal interactome of the luteinizing hormone receptor (LHR) and identifies novel interactors like RAP2B that modulate receptor signaling and trafficking.

LHR and Gαs trafficking drive sustained cAMP signalling from endosomes to control steroidogenesis

This study shows that LHR and Gαs trafficking from endosomes sustain cAMP signaling to control steroidogenesis in Leydig cells.

Mechanistic basis for GPCR phosphorylation-dependent allosteric signaling specificity of β-arrestin 1 and 2

This study maps how phosphorylation patterns shape β-arrestin structure and function using simulations and machine learning, revealing isoform-specific allosteric responses and effector engagement.

Structural Basis for the Activation of Proteinase-Activated Receptors (PARs) by Endogenous Ligands

This study presents structural insights into PAR1 and PAR2 activation by endogenous ligands, revealing a novel mechanism and potential targets for therapeutic development.

Inactive structures of the vasopressin V2 receptor reveal distinct antagonist binding modes for Tolvaptan and Mambaquaretin toxin

The paper solves cryo-EM structures of the V2R bound to Tolvaptan and Mambaquaretin toxin, revealing distinct antagonist binding modes and inactive conformations.

Unveiling G-Protein-Coupled Receptor Conformational Dynamics via Metadynamics Simulations and Markov State Models

This study uses metadynamics and Markov state models to explore the conformational dynamics of GHSR-1a, revealing ligand-dependent metastable states and intermediate structures.

Opioid receptors reveal a discrete cellular mechanism of endosomal G protein activation

This study shows that the mu-opioid receptor increases endosomal G protein activity without requiring receptor internalization or endosomal activation.

GPCRchimeraDB: A database of chimeric G protein-coupled receptors (GPCRs) to assist their design

Resource of 212 literature-curated chimeric class A GPCRs linked to 1,755 natural class A mammalian GPCRs, annotated at sequence, structure and biophysics level, with guidelines for designing new chimeras.

Allosteric modulation of dimeric GPR3 by ligands in the dimerization interface

This study determines cryo-EM structures of GPR3 in active and inactive states, revealing dimerization mechanisms and identifying a negative allosteric modulator targeting the dimerization interface.

The 4th GPCR Dock: assessment of blind predictions for GPCR-ligand complexes in the era of AlphaFold

This paper assesses GPCR-ligand complex predictions in the era of AlphaFold, showing AI models can match or exceed low-resolution experimental structures but still need high-resolution data and hybrid methods.

Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD)

This paper introduces mwSuMD, a molecular dynamics algorithm, to simulate complex structural transitions in GPCRs without energy bias, demonstrating its application in studying receptor activation and GDP release.

Antimuscarinic drugs exert β-arrestin-biased agonism at the muscarinic acetylcholine type 1 receptor

Antimuscarinic drugs act as β-arrestin-biased agonists via casein kinase 2 activation to promote ERK1/2 phosphorylation and neurite outgrowth.

P-Rex1 Limits the Agonist-Induced Internalisation of GPCRs Independently of its Rac-GEF Activity

This paper shows P-Rex1 limits agonist-induced GPCR internalisation through its PDZ, DEP, and IP4P domains, independent of its Rac-GEF activity, by inhibiting phosphorylation and interacting with Grk2.

Quantification of Signal Amplification for Receptors: The Kd/EC50 Ratio of Full Agonists as a Gain Parameter

The paper introduces the Kd/EC50 ratio as a gain parameter to quantify signal amplification for full agonists, clarifying the relationship between receptor occupancy and response.

Lipid-Mediated Modulation of mGluR2 Embedded in Micelle and Bilayer Environments: Insights from Molecular Dynamics

This study uses molecular dynamics simulations to show that CHS concentration affects mGluR2's structural stability and conformational dynamics in micelle and bilayer environments.

Activation and signaling characteristics of the hydroxy-carboxylic acid 3 receptor identified in human neutrophils through a microfluidic flow cell technique

This study identifies HCA3R as a new GPCR in human neutrophils and shows it activates NADPH oxidase with specific pre-treatment requirements.

LTB4 is converted into a potent human neutrophil NADPH oxidase activator via a receptor transactivation mechanism in which the BLT1 receptor activates the free fatty acid receptor 2

This study shows that an allosteric modulator of FFA2R converts LTB4 into a potent NADPH oxidase activator via BLT1R-FFA2R receptor transactivation.

A Putative Binding Model of Nitazene Derivatives at the mu-Opioid Receptor

This paper uses computational methods to model how nitazene derivatives bind to the mu-opioid receptor, identifying key binding modes and interactions.

Revealing molecular determinants of ligand efficacy and affinity at the D2 dopamine receptor through molecular dynamics simulations

This study uses molecular dynamics simulations to uncover the molecular mechanisms of ligand activation in the D2 dopamine receptor and identifies differences in activation mechanisms between dopamine and adrenergic receptors.

FAST RESENSITIZATION OF G PROTEIN-COUPLED RECEPTORS REQUIRESTHEIR PI(4,5)P2-DEPENDENT SORTING INTO AN AP2 POSITIVE COMPARTMENT

This study shows that GPCRs regain G protein signaling without endocytosis by sorting into an AP2-positive plasma membrane compartment, regulated by PI(4,5)P2 and beta-arrestins.

CCR9 signal termination is governed by an arrestin-independent phosphorylation mechanism

This study identifies an arrestin-independent phosphorylation mechanism that terminates CCR9 signaling, revealing a novel regulatory pathway for GPCR function.

High resolution deep mutational scanning of the melanocortin-4 receptor enables target characterization for drug discovery

This study applies high-resolution deep mutational scanning to the melanocortin-4 receptor to identify functionally significant variants and guide drug development.

Direct detection of endogenous Gαi activity in cells with a sensitive conformational biosensor

This paper introduces an optical biosensor that directly detects endogenous Gαi activity in cells, showing improved sensitivity and reduced interference compared to existing methods.

Extracellular Nanobody Screening using Conformationally Stable GPCR

The paper stabilizes GPCRs in specific conformations using a fusion protein and screens nanobodies to identify conformation-specific binders.