7T94

Cryo-EM structure of S1 state ACh-bound M2R-Go signaling complex with a PAM

Summary for 7T94

• Entry DOI: 10.2210/pdb7t94/pdb
• EMDB information: 25751
• Descriptor: Muscarinic acetylcholine receptor M2,muscarinic acetylcholine receptor M2 chimera, Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (8 entities in total)
• Functional Keywords: gpcr, signaling complex, muscarinic receptor, acetylcholine, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 153348.39

Authors

Xu, J.,Wang, Q.,Du, Y.,Kobilka, B.K. (deposition date: 2021-12-17, release date: 2023-01-25, Last modification date: 2024-11-06)

Primary citation

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, B.K.
Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.
Nat Commun, 14:376-376, 2023

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-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.

PubMed: 36690613
DOI: 10.1038/s41467-022-35726-z

Experimental method

ELECTRON MICROSCOPY (3.16 Å)