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

Wessel A. C. Burger, Vi Pham, Ziva Vuckovic, Alexander S. Powers, Jesse I. Mobbs, Yianni Laloudakis, Alisa Glukhova, Denise Wootten, Andrew B. Tobin, Patrick M. Sexton, Steven M. Paul, Christian C. Felder, Radostin Danev, Ron O. Dror (), Arthur Christopoulos (), Celine Valant () and David M. Thal ()
Additional contact information
Wessel A. C. Burger: Monash University
Vi Pham: Monash University
Ziva Vuckovic: Monash University
Alexander S. Powers: Stanford University
Jesse I. Mobbs: Monash University
Yianni Laloudakis: Stanford University
Alisa Glukhova: Monash University
Denise Wootten: Monash University
Andrew B. Tobin: University of Glasgow
Patrick M. Sexton: Monash University
Steven M. Paul: Karuna Therapeutics
Christian C. Felder: Karuna Therapeutics
Radostin Danev: University of Tokyo
Ron O. Dror: Stanford University
Arthur Christopoulos: Monash University
Celine Valant: Monash University
David M. Thal: Monash University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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 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.

Date: 2023
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DOI: 10.1038/s41467-023-41199-5

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