Crystal structure of the M5 muscarinic acetylcholine receptor.

Proceedings of the National Academy of Sciences of the United States of America 2019 Dec 17

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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. Copyright © 2019 the Author(s). Published by PNAS.

Citation

Ziva Vuckovic, Patrick R Gentry, Alice E Berizzi, Kunio Hirata, Swapna Varghese, Geoff Thompson, Emma T van der Westhuizen, Wessel A C Burger, Raphaël Rahmani, Celine Valant, Christopher J Langmead, Craig W Lindsley, Jonathan B Baell, Andrew B Tobin, Patrick M Sexton, Arthur Christopoulos, David M Thal. Crystal structure of the M5 muscarinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the United States of America. 2019 Dec 17;116(51):26001-26007