Receptor Mechanisms and Signaling

This study presents cryo-EM structures of GPR99/OXGR1 with oxoglutarate and LTE4, revealing distinct binding sites and signaling mechanisms.

This study investigates ADGRG1 activation mechanisms through mechanical and allosteric pathways, showing force direction determines signaling via GAIN domain dynamics and introducing engineered variants with tailored sensitivity.

This study designs GPCR variants with reprogrammed ligand-selective signaling using computational methods, showing sequence variations impact ligand potency and efficacy.

This study identifies AngII analogs with modified C-terminal peptides that selectively engage Gq or β-arrestin pathways, showing differential effects on cardiac function and blood pressure in rats.

XenoSignal assesses ligand-receptor interactions across species using AlphaFold3 predictions to improve understanding of tumor-microenvironment crosstalk in xenograft models.

The paper identifies amphipathic helix 8 as a driver of constitutive GPCR endocytosis through membrane curvature association.

The paper investigates the G protein coupling profile of dopamine D3 receptor, finding it selectively activates Go and Gz subtypes but not Gi proteins, with structural determinants identified.

This paper introduces GTACs, bispecific antibodies that selectively downregulate GPCRs via endocytosis and lysosomal degradation, showing high potency and selectivity for therapeutic targets.

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

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

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

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

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

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

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.

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.

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

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.

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

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

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

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

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.

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.

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.

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.

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.

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.

The paper investigates how multiple triggers on an allosteric communication network influence preferential coupling of the CB2R to Gi2 over β-arrestin1, revealing insights into GPCR signaling mechanisms.