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- W4317804518 abstract "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-arrestin pathways. Structural and spectroscopic analysis suggest that LY211620 stabilizes distinct intracellular conformational ensembles from agonist-bound M2R, which may enhance β-arrestin recruitment while impairing G-protein activation. These results highlight the role of conformational dynamics in the complex signaling behavior of GPCRs, and could facilitate design of better drugs." @default.
- W4317804518 created "2023-01-24" @default.
- W4317804518 creator A5001320387 @default.
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- W4317804518 date "2023-01-23" @default.
- W4317804518 modified "2023-09-26" @default.
- W4317804518 title "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor" @default.
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- W4317804518 doi "https://doi.org/10.1038/s41467-022-35726-z" @default.
- W4317804518 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36690613" @default.
- W4317804518 hasPublicationYear "2023" @default.
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