Xu J, Wang Q, Hübner H, Hu Y, Niu X, Wang H, Maeda S, Inoue A, Tao Y, Gmeiner P, Du Y, Jin C, Kobilka BK (2023)
Publication Type: Journal article
Publication year: 2023
Book Volume: 14
Article Number: 376
Journal Issue: 1
DOI: 10.1038/s41467-022-35726-z
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.
APA:
Xu, J., Wang, Q., Hübner, H., Hu, Y., Niu, X., Wang, H.,... Kobilka, B.K. (2023). Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature Communications, 14(1). https://doi.org/10.1038/s41467-022-35726-z
MLA:
Xu, Jun, et al. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor." Nature Communications 14.1 (2023).
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