Receptor Mechanisms and Signaling

This study presents cryo-EM structures of GPR17 with ligands and shows orthosteric and allosteric binding mechanisms, suggesting alternative approaches for drug discovery.

The paper shows that nuclear α1A-adrenergic receptors inhibit βAR-mediated cAMP production via an inside-out MAPK signaling pathway in cardiac myocytes, revealing a novel mechanism of sympathetic signaling interaction.

The paper shows MT1, a Gi-coupled receptor, can also couple to Gs proteins, activates the Gs/cAMP pathway under long-term melatonin exposure, and presents the first solved structure of a Gi-coupled receptor-Gs complex.

This study shows that LY294002 and LY303511 affect serotonin-induced Ca2+ signaling via distinct mechanisms involving the 5-HT2C receptor, suggesting off-target effects beyond their intended PI3K inhibition.

This study shows that phosphorylation of specific C-terminal serine doublets in the GLP-1R is critical for receptor signaling in β-cells, with basal phosphorylation influencing receptor dynamics and signaling outcomes.

The paper introduces a coarse-grained MD approach to simulate competitive ligand binding at the adenosine A2A receptor, revealing cooperative mechanisms in ligand competition.

This study reveals an atypical activation mechanism of CXCR7, identifies its role as an opioid receptor, and highlights potential for novel pain therapeutics.

This study shows that the free fatty acid 2 receptor modulates C5a receptor signaling, enhancing NADPH oxidase activation and reducing the effect of the antagonist avacopan.

The paper presents a thermodynamic model explaining super-additivity in similar drug combinations, with implications for cysteine-derived compounds and opioid withdrawal treatment.

The paper identifies multiple allosteric sites on the D1 dopamine receptor that allow synergistic enhancement of GPCR signaling through combined positive allosteric modulators.

The paper shows that AP-7-168 induces β2AR dimerization by acting as a molecular glue, revealing a new allosteric mechanism for GPCR modulation.

This study identifies a hydration network in GPR174 that drives receptor activation and G protein selectivity through structural and functional analyses.

The vasopressin V2 receptor activates G proteins and β-arrestins at the lysosomal surface before being degraded.

The paper determines the cryo-EM structure of ADGRL4 coupled to Gq, showing weak Gq coupling and distinct interactions compared to other GPCRs, supporting its role in cancer.

RareFoldGPCR designs peptide agonists using noncanonical amino acids to modulate GPCRs, validated experimentally for functional activity.

The paper introduces a platform to characterize GPCR expression and uses machine learning to identify structural features affecting their biosynthesis.

This study models GPR174 bound to an antagonist and compares its dynamics to LysoPS, revealing distinct ligand-specific mechanisms and potential for immunotherapeutic antagonists.

This study investigates the mechanotransduction mechanism of ADGRG1/GPR56, revealing a dual-mode activation process that does not require NTF-CTF dissociation and depends on the Stachel element.

This study compares ligand affinities at 5-HT7 receptors using standard buffer vs. artificial brain extracellular fluid, finding that temperature and buffer composition significantly affect antagonist/inverse agonist affinities but not agonist affinity.

This study captures time-resolved structures of β2AR modulated by a photoswitchable beta-blocker, revealing conformational changes linked to ligand isomerization and receptor function.

This study investigates the K53N mutation in Gs isoforms, revealing isoform-specific loss- and gain-of-function effects contributing to disease mechanisms in endocrine and cardiac tissues.

The paper explains how bivalent insulin receptor ligands act as antagonists or agonists based on the order of their binding sites, using cryo-EM structures.

This paper shows that β1- and β2-adrenergic receptor haplotypes influence responses to bucindolol and placebo in heart failure patients, with internalizing haplotypes providing protection and bucindolol being effective in internalization-resistant ones.

This study identifies a novel GIPR trafficking pathway involving myosin VI and β-arrestin, showing their synergistic role in receptor internalization, signaling, and insulin response in pancreatic beta cells.

This study investigates how aromatic amino acids in the orthosteric region of CB1 regulate conformational transitions using molecular dynamics simulations, revealing their roles in stabilizing active states and modulating receptor dynamics.

This paper computationally designs soluble CCR8 analogues that retain native antibody binding, achieving a 62% success rate with preserved structural and functional properties.

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.