7t90

Cryo-EM structure of ACh-bound M2R-Go signaling complex in S2 state

spinqualitylabelsall models 7t90, resolution 3.32Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7t90 is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.32Å Ligands: ACH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ACM2_HUMAN Disease susceptibility is associated with variations affecting the gene represented in this entry. Function ACM2_HUMAN The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Publication Abstract from PubMed 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 beta-arrestin pathways. Structural and spectroscopic analysis suggest that LY211620 stabilizes distinct intracellular conformational ensembles from agonist-bound M2R, which may enhance beta-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. Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.,Xu J, Wang Q, Hubner H, Hu Y, Niu X, Wang H, Maeda S, Inoue A, Tao Y, Gmeiner P, Du Y, Jin C, Kobilka BK Nat Commun. 2023 Jan 23;14(1):376. doi: 10.1038/s41467-022-35726-z. PMID:36690613 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Muscarinic acetylcholine receptor Transducin 3D structures

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