{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["14(1)"],"submitter":["Xu J"],"pubmed_abstract":["The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiological agonist iperoxo, as well as a positive allosteric modulator LY2119620. These studies reveal that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, where two conformers with distinctive G-protein orientations were determined. We find that LY2119620 increases the affinity for both agonists, but differentially modulates agonists efficacy in G-protein and β-arrest"],"journal":["Nature communications"],"pagination":["376"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9870890"],"repository":["biostudies-literature"],"pubmed_title":["Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor."],"pmcid":["PMC9870890"],"pubmed_authors":["Hu Y","Maeda S","Hubner H","Du Y","Wang H","Xu J","Niu X","Wang Q","Inoue A","Tao Y","Jin C","Gmeiner P","Kobilka BK"],"additional_accession":[]},"is_claimable":false,"name":"Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.","description":"The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiological agonist iperoxo, as well as a positive allosteric modulator LY2119620. These studies reveal that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, where two conformers with distinctive G-protein orientations were determined. We find that LY2119620 increases the affinity for both agonists, but differentially modulates agonists efficacy in G-protein and β-arrest","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2026-05-27T10:51:16.098Z","creation":"2025-04-04T11:26:21.724Z"},"accession":"S-EPMC9870890","cross_references":{"pubmed":["36690613"],"doi":["10.1038/s41467-022-35726-z"]}}