Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor

Jun Xu, Qinggong Wang, Harald Hübner, Yunfei Hu, Xiaogang Niu, Haoqing Wang, Shoji Maeda, Asuka Inoue, Yuyong Tao, Peter Gmeiner, Yang Du (), Changwen Jin () and Brian K. Kobilka ()
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Jun Xu: Stanford University School of Medicine
Qinggong Wang: Chinese University of Hong Kong
Harald Hübner: Friedrich-Alexander University
Yunfei Hu: Peking University
Xiaogang Niu: Peking University
Haoqing Wang: Stanford University School of Medicine
Shoji Maeda: Stanford University School of Medicine
Asuka Inoue: Tohoku University
Yuyong Tao: University of Science and Technology of China
Peter Gmeiner: Friedrich-Alexander University
Yang Du: Chinese University of Hong Kong
Changwen Jin: Peking University
Brian K. Kobilka: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

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.

Date: 2023
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DOI: 10.1038/s41467-022-35726-z

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