Dataset Information

Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq

ABSTRACT: Muscarinic acetylcholine receptor M3 (M3) and its downstream effector Gq/11 are critical drug development targets given their involvement in numerous physiological processes and diseases. Although a cryo-electron microscopy study previously defined the structure of the M3-miniGq complex, the lack of information on the intracellular loop 3 (ICL3) of M3 and α-helical domain (AHD) of Gαq has made it difficult to comprehend the molecular mechanism of M3-Gq coupling fully. Here, we present the molecular mechanism underlying the dynamic interactions between the wild-type full-length M3 and heterotrimeric Gq using hydrogen-deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cell systems. This study suggests potential binding interfaces between M3 and Gq in pre-assembled and fully active nucleotide-free complexes. In addition to well-known binding interfaces, we observed the interaction of long ICL3 with Gβγ. Furthermore, M3 ICL3 negatively affected M3-Gq coupling, and the Gαq AHD underwent unique conformational changes during M3-Gq coupling. Therefore, we propose a comprehensive molecular mechanism of M3-Gq coupling by analyzing previously well-defined binding interfaces and neglected regions, such as M3 ICL3 and the Gαq AHD.

INSTRUMENT(S): Xevo G2 Q-Tof, Xevo G2-XS QTof

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Donghee Ham

LAB HEAD: Ka Young

PROVIDER: PXD042562 | Pride | 2024-05-22

REPOSITORIES: Pride

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Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq.

Ham Donghee D Inoue Asuka A Xu Jun J Du Yang Y Chung Ka Young KY

Communications biology 20240323 1

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 ...[more]

PMID: 38521872

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Dataset Information

Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq

Publications

Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq.

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