Cryo-EM reveals an extrahelical allosteric binding site at the M₅ mAChR.

ABSTRACT: The M₅ muscarinic acetylcholine receptor (M₅ mAChR) represents a promising therapeutic target for neurological disorders. However, the high conservation of its orthosteric binding site poses significant challenges for drug development. While selective positive allosteric modulators (PAMs) offer a potential solution, a structural understanding of the M₅ mAChR and its allosteric binding sites remains limited. Here, we present a 2.8 Å cryo-electron microscopy structure of the M₅ mAChR complexed with heterotrimeric G_q protein and the agonist iperoxo, completing the active-state structural characterization of the mAChR family. To identify the binding site of M₅-selective PAMs, we implement an integrated approach combining mutagen

SUBMITTER: Burger WAC 

PROVIDER: S-EPMC12314052 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature