Receptor Mechanisms and Signaling

A Genome-wide CRISPR Screen Reveals ZDHHC8-Dependent Gαq Palmitoylation as a Key Regulator of GPCR Signaling

The paper identifies ZDHHC8-dependent Gαq palmitoylation as a critical regulator of GPCR signaling through a genome-wide CRISPR screen in Drosophila.

Antagonistic insulin mimetics lock the insulin receptor in an alternative apo-state

This paper reveals how insulin mimetics stabilize the insulin receptor in a novel apo-state that prevents activation by blocking signal transduction.

The CryoEM Structure of Human GPR75: Insights into ECL2-Mediated Activation

The paper presents the cryoEM structure of unliganded human GPR75 and functional data showing its active-like state and signaling properties.

Non-canonical internalization mechanisms of mGlu receptors

This study identifies non-canonical internalization mechanisms for mGlu receptors, showing some require neither GRKs nor beta-arrestins for agonist-induced internalization.

An online GPCR drug discovery resource

The paper introduces an online resource for GPCR drugs, clinical trial agents, and disease indications to aid in drug discovery and target prioritization.

Optimization of the prostaglandin F2α receptor for structural biology

This paper optimizes the prostaglandin F2α receptor (FP) for structural biology by improving its purification yield and in vitro stability through protein engineering.

Imaging and quantifying cytoplasmic tail dynamics of membrane receptors in living cells

This study develops a single-molecule technique to investigate cytoplasmic tail dynamics of membrane receptors in living cells, revealing ligand-induced activation mechanisms of β2AR.

The Unique Role of Intracellular Perinuclear β-Adrenergic Receptors in defining Signaling Compartmentation and Pathological Cardiac Remodeling

This study identifies Golgi-localized β-adrenergic receptors as critical for cAMP and calcium signaling, pathological gene transcription, and cardiomyocyte hypertrophy, offering a new therapeutic target for Dilated Cardiomyopathy.

De novo Design of A Fusion Protein Tool for GPCR Research

This paper introduces a de novo design strategy called 'click fusion' to create stable GPCR fusion proteins, enabling structural studies via cryo-EM.

Multi-Coloured Sequential Resonance Energy Transfer for Simultaneous Ligand Binding at G Protein-Coupled Receptors

The paper develops a method to study simultaneous ligand binding at GPCRs using multi-colored sequential resonance energy transfer and applies it to the FFA1 receptor.

Cytoplasmic tail composition modulates the G protein and arrestin-3 signaling bias of the adhesion GPCR LPHN2

This study shows that the C-terminal tail of LPHN2 modulates G protein and arrestin-3 signaling bias through alternative splicing and GRK interactions.

The c-Src inhibitor eCF506 diminishes opioid tolerance creating bias against β-arrestin2 recruitment

The paper tests eCF506, a c-Src inhibitor, showing it reduces opioid tolerance by decreasing β-arrestin2 recruitment without affecting cAMP inhibition.

A small molecule enhances arrestin-3 binding to the β2-adrenergic receptor

A small molecule stabilizes the pre-activated state of arrestin-3, enhancing its binding to phosphorylation-deficient β2-adrenergic receptors.

Ligand-dependent G protein dynamics underlying opioid signaling efficacy

This study uses smFRET to show that opioid ligands modulate Gi protein conformational dynamics, with higher-efficacy agonists promoting open, low-nucleotide-affinity states.

Protein Frustration Reveals Active Sites in Co-Evolved GPCR:G Protein Complexes and in Engineered Targeted Degrader Complexes

The paper identifies frustrated residues in GPCR:G protein interfaces and engineered degrader complexes, showing higher frustration in engineered interfaces.

Constant-pH simulation of the human β2 adrenergic receptor inactivation

This study uses constant-pH simulations to show that β2AR inactivation is linked to protonation events and sodium ion interactions, challenging existing models of GPCR function.

Translation-independent association of mRNAs encoding protomers of the 5-HT2A-mGlu2 receptor complex in living cells

The paper shows that mRNAs for 5-HT2A and mGlu2 receptors associate co-translationally without requiring their encoded proteins, using in vitro and ex vivo experiments.

Molecular Mechanism of pH Sensing and Activation in GPR4 Reveals Proton-Mediated GPCR Signaling

This study reveals the molecular mechanism of pH sensing and activation in GPR4 through cryo-EM structures, showing proton-driven conformational changes and lipid modulation.

AI-Driven Virtual Screening and First-in-Class Conformational Biosensor Enable the Discovery of a GPR183 Inverse Agonist

The paper discovers a GPR183 inverse agonist using AI-driven virtual screening and a conformational biosensor, showing inhibition of Gi activation and β-arrestin2 recruitment.

Plasma membrane rather than endosomal Gq signaling drives transcriptional activity by the viral chemokine receptor US28 in glioblastoma

The paper shows that US28's Gq/11 signaling from the plasma membrane, not endosomes, primarily drives gene expression related to glioblastoma proliferation and inflammation.

Differential role of phosphorylation in glucagon family receptor signaling revealed by mass spectrometry

This study identifies phosphorylated C-tail residues in glucagon family GPCRs and shows their differential effects on βarr recruitment and cAMP production across GLP-1R, GCGR, and GIPR.

Conformational dynamics of the active state of β-arrestin 1

This study uses molecular dynamics simulations to investigate the conformational changes in β-arrestin 1 during activation by the vasopressin receptor-2.

G protein subtype preference dictates paroxetine-enhanced serotonin receptor response in normal breast epithelial cells

This study shows that paroxetine enhances serotonin receptor responses in breast epithelial cells by modulating G protein subtype-specific signaling pathways, leading to reduced cell proliferation.

Constitutive activation and allosteric mechanisms underlying Gi/Gq signaling bias in SUCNR1 revealed by AlphaFold-based modeling and enhanced sampling simulations

This study uses AlphaFold and simulations to show human SUCNR1 spontaneously adopts active conformations and exhibits constitutive signaling, while murine SUCNR1 requires agonist for activation.

Membrane phosphoinositides allosterically tune β-arrestin dynamics to facilitate GPCR core engagement

This study reveals that membrane phosphoinositides allosterically regulate β-arrestin dynamics, enabling engagement with minimally phosphorylated GPCRs.

Hidden Bias: GPCR Polymorphisms and the Genomic Landscape of β- Arrestin Signaling

The paper identifies SNPs in GPCRs that alter β-arrestin signaling bias and shows their potential impact on phenotypic variation.

THE ACTIN CYTOSKELETON CONTROLS NADPH OXIDASE ACTIVATION AND G PROTEIN RECRUITMENT MEDIATED BY NEUTROPHIL G-alpha-q-COUPLED RECEPTORS

This paper shows that the actin cytoskeleton regulates NADPH oxidase activation and G protein recruitment in neutrophils via Gq-coupled receptors.

GPCR-MAPS: high-resolution functional and allosteric mapping of G protein-coupled receptor activation and bias

The paper introduces GPCR-MAPS, a method to generate high-resolution functional and allosteric maps of GPCRs, revealing modular architecture and novel allosteric pockets.

Gαs-specific structural elements attenuate interactions with RGS proteins

The paper identifies structural elements in Gαs that prevent interactions with RGS proteins, showing three residues in the GTPase domain are necessary and sufficient for this resistance.

Molecular fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors

This study identifies a convergent molecular mechanism and species-specific pharmacology in complement anaphylatoxin receptors through structural and functional analyses of ligand-receptor interactions.