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

Author:

Burger Wessel A. C.ORCID,Pham Vi,Vuckovic Ziva,Powers Alexander S.,Mobbs Jesse I.ORCID,Laloudakis Yianni,Glukhova AlisaORCID,Wootten DeniseORCID,Tobin Andrew B.ORCID,Sexton Patrick M.ORCID,Paul Steven M.,Felder Christian C.,Danev RadostinORCID,Dror Ron O.ORCID,Christopoulos ArthurORCID,Valant CelineORCID,Thal David M.ORCID

Abstract

AbstractThe 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 Gi1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M4 mAChR, with one molecule bound in the orthosteric (acetylcholine-binding) site and a second molecule in an extracellular vestibular allosteric site. Molecular dynamic simulations supports the structural findings, and pharmacological validation confirmed that xanomeline acts as a dual orthosteric and allosteric ligand at the human M4 mAChR. These findings provide a basis for further understanding xanomeline’s complex pharmacology and highlight the myriad of ways through which clinically relevant ligands can bind to and regulate GPCRs.

Funder

Department of Health | National Health and Medical Research Council

Department of Education and Training | Australian Research Council

Wellcome Trust

MEXT | Japan Society for the Promotion of Science

U.S. Department of Health & Human Services | National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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