Crystal structure of the M5 muscarinic acetylcholine receptor

Vuckovic, Z. et al. (2019) Crystal structure of the M5 muscarinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America, 116(51), pp. 26001-26007. (doi: 10.1073/pnas.1914446116) (PMID:31772027) (PMCID:PMC6926013)

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The human M5 muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, a lack of structural information for this receptor subtype has limited further drug development and validation. Here we report a high-resolution crystal structure of the human M5 mAChR bound to the clinically used inverse agonist, tiotropium. This structure allowed for a comparison across all 5 mAChR family members that revealed important differences in both orthosteric and allosteric sites that could inform the rational design of selective ligands. These structural studies, together with chimeric swaps between the extracellular regions of the M2 and M5 mAChRs, provided structural insight into kinetic selectivity, where ligands show differential residency times between related family members. Collectively, our study provides important insights into the nature of orthosteric and allosteric ligand interaction across the mAChR family that could be exploited for the design of selective drugs.

Item Type:Articles
Keywords:Kinetics, Drug design, Muscarinic receptor, Crystal structure, G protein-coupled receptor
Glasgow Author(s) Enlighten ID:Tobin, Andrew
Authors: Vuckovic, Z., Gentry, P. R., Berizzi, A. E., Hirata, K., Varghese, S., Thompson, G., van der Westhuizen, E. T., Burger, W. A. C., Rahmani, R., Valant, C., Langmead, C. J., Lindsley, C. W., Baell, J. B., Tobin, A. B., Sexton, P. M., Christopoulos, A., and Thal, D. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN (Online):1091-6490
Published Online:26 November 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in PNAS 116(51):26001-26007
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173304Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOTR)201529/Z/16/ZMCSB - Molecular Pharmacology