Crystal structure of the M5 muscarinic acetylcholine receptor

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

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)26001-26007
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number51
DOIs
Publication statusPublished - 17 Dec 2019

Keywords

  • Crystal structure
  • Drug design
  • G protein-coupled receptor
  • Kinetics
  • Muscarinic receptor

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