EMD-25748
Cryo-EM structure of ACh-bound M2R-Go signaling complex in S1 state
EMD-25748
Single-particle3.21 Å
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Map released: 25/01/2023
Last modified: 06/11/2024
Sample Organism:
Homo sapiens,
Mus musculus
Sample: ACh-bound M2R-GoA-scFv16 complex
Fitted models: 7t8x (Avg. Q-score: 0.517)
Deposition Authors: Xu J
,
Wang Q,
Du Y
,
Kobilka BK
Sample: ACh-bound M2R-GoA-scFv16 complex
Fitted models: 7t8x (Avg. Q-score: 0.517)
Deposition Authors: Xu J
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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
(2023) Nat Commun , 14 , 376 - 376
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(2023) Nat Commun , 14 , 376 - 376
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.
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.