Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq.

Donghee Ham, Asuka Inoue, Jun Xu, Yang Du, Ka Young Chung

Communications biology 2024 Mar 23

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Muscarinic acetylcholine receptor M3 (M3) and its downstream effector Gq/11 are critical drug development targets due to their involvement in physiopathological processes. Although the structure of the M3-miniGq complex was recently published, the lack of information on the intracellular loop 3 (ICL3) of M3 and extensive modification of Gαq impedes the elucidation of the molecular mechanism of M3-Gq coupling under more physiological condition. Here, we describe the molecular mechanism underlying the dynamic interactions between full-length wild-type M3 and Gq using hydrogen-deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cell systems. We propose a detailed analysis of M3-Gq coupling through examination of previously well-defined binding interfaces and neglected regions. Our findings suggest potential binding interfaces between M3 and Gq in pre-assembled and functionally active complexes. Furthermore, M3 ICL3 negatively affected M3-Gq coupling, and the Gαq AHD underwent unique conformational changes during M3-Gq coupling. © 2024. The Author(s).

Citation

Donghee Ham, Asuka Inoue, Jun Xu, Yang Du, Ka Young Chung. Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq. Communications biology. 2024 Mar 23;7(1):362