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

WAC Burger; V Pham; Z Vuckovic; AS Powers; JI Mobbs; Y Laloudakis; A Glukhova; D Wootten; AB Tobin; PM Sexton; SM Paul; CC Felder; R Danev; RO Dror; A Christopoulos; C Valant; DM Thal

Journal article

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

WAC Burger, V Pham, Z Vuckovic, AS Powers, JI Mobbs, Y Laloudakis, A Glukhova, D Wootten, AB Tobin, PM Sexton, SM Paul, CC Felder, R Danev, RO Dror, A Christopoulos, C Valant, DM Thal

Nature Communications | NATURE PORTFOLIO | Published : 2023

DOI: 10.1038/s41467-023-41199-5

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 ..

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University of Melbourne Researchers

Alisa Glukhova Author

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Grants

Awarded by National Science Foundation

Funding Acknowledgements

This work was funded with support by a Wellcome Trust Collaborative Award (201529/Z/16/Z: P.M.S., A.B.T., A.C.), the National Health and Medical Research Council of Australia (1055134: A.C., P.M.S.; 1150083: P.M.S., A.C.; and 1138448: D.M.T.), the Australian Research Council (DE170100152: D.M.T.; DP190102950: C.V., A.C., and IC200100052: P.M.S., D.W.), the National Institutes of Health (R01GM127359: R.O.D.), the National Science Foundation Graduate Research Fellowship (A.S.P.), and Karuna Therapeutics. P.M.S. is a Senior Principal Research Fellow (1154434), D.W. a Senior Research Fellow (1155302), D.M.T. an Early Career Research Fellow (1196951). R.D. was supported by Japan Society for the Promotion of Science (JSPS) Kakenhi grant (22H02554). This work was partially supported by the Monash University Ramaciotti Centre for cryo-electron microscopy and the Monash University MASSIVE high-performance computing facility and supercomputing resources.