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Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):26001-26007. doi: 10.1073/pnas.1914446116. Epub 2019 Nov 26.

Crystal structure of the M5 muscarinic acetylcholine receptor.

Author information

1
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
2
RIKEN SPring-8 Center, 1-1-1 Kouto, Sayo, Hyogo 679-5148, Japan.
3
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
4
Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232.
5
Department of Chemistry, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232.
6
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom.
7
School of Pharmacy, Fudan University, 201203 Shanghai, China.
8
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; arthur.christopoulos@monash.edu david.thal@monash.edu.

Abstract

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.

KEYWORDS:

G protein-coupled receptor; crystal structure; drug design; kinetics; muscarinic receptor

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