Xanomeline displays concomitant orthosteric and allosteric binding modes at the M₄ mAChR.

ABSTRACT: The M₄ muscarinic acetylcholine receptor (M₄ mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M₄ mAChR in complex with the heterotrimeric G_i1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M₄ mAChR, with one molecule bound in the orthosteric (acetylchol

SUBMITTER: Burger WAC 

PROVIDER: S-EPMC10482975 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature