Receptor Mechanisms and Signaling

This study synthesizes and evaluates 4-(hexyloxy)benzoate derivatives to optimize muscarinic receptor antagonists, finding that rigid groups increase affinity but reduce duration, while flexible analogues balance potency and residence time.

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 paper investigates the allosteric mechanism of GPCRs, finding that both peptide- and small-molecule-activated GPCRs use an induced-fit mechanism rather than conformational selection.

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.

This study identifies D2R receptor mutants that stabilize oligomers and show biased recruitment of β-arrestin-2, leading to altered signaling outcomes.

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

This study shows that MRAP2 modifies MC4R signaling and oligomerization, enhancing G protein signaling while reducing beta-arrestin2 recruitment and receptor internalization.

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 introduces a nanobody sensor to detect conformational changes in beta-arrestins upon GPCR activation, revealing receptor-specific conformational diversity.

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 uses molecular dynamics simulations to investigate how different ligands affect 5-HT2AR activation, finding that excessive activation causes hallucinations while modest activation may yield antidepressant effects.

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.

This study identifies a shared non-canonical cholesterol-binding site at TM6 in muscarinic and opioid receptors, with significant implications for drug development targeting tissue-specific GPCR modulation.

This study uses cryo-EM and HDX-MS to analyze GPBAR1-G protein interactions, revealing conformational dynamics and structural details of the complex.

The paper determines the cryo-EM structure of a full-length human β1-adrenergic receptor in complex with Gs, revealing structural insights into ICL3's role in G protein activation.

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 identifies and validates non-covalent inhibitors of RGS14 GAP activity using structure-guided virtual screening and machine learning, showing improved potency and CNS penetration.

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.

RAMP3 complexes with GLP-1R at the plasma membrane, shifts signalling toward Ca2+ mobilisation, and enhances insulin secretion in INS-1 832/3 cells; Ramp3 loss blunts GLP-1 responses in mice.

The paper investigates how amylin receptor subunit interactions are modulated by agonists and how these interactions influence cAMP signaling.

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.