EMD-25748

Single-particle
3.21 Å
EMD-25748 Deposition: 17/12/2021
Map released: 25/01/2023
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-25748

Cryo-EM structure of ACh-bound M2R-Go signaling complex in S1 state

EMD-25748

Single-particle
3.21 Å
EMD-25748 Deposition: 17/12/2021
Map released: 25/01/2023
Last modified: 06/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
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
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
PUBMED: 36690613
DOI: doi:10.1038/s41467-022-35726-z
ISSN: 2041-1723
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.