Discovering Key Activation Hotspots in the M₂ Muscarinic Receptor.

ABSTRACT: The M₂ muscarinic receptor (M₂R) is a prototypical G protein-coupled receptor (GPCR) that serves as a model system for understanding ligand recognition and GPCR activation. Here, using vibrational spectroscopy, we identify the mechanisms governing M₂R activation by its native agonist, acetylcholine. Combined with mutagenesis, computational chemistry, and organic synthetic chemistry, our analyses found that the precise distance between acetylcholine and Asn404, one of the amino acids constituting the ligand-binding site, is important for M₂R activation and that the N404Q mutant undergoes partial active state-like conformational changes. We discovered that a water molecule bridging acetylcholine and Asn404 forms a precise and flexible hydrogen bond

SUBMITTER: Sugiura Y 

PROVIDER: S-EPMC11987023 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature