Crystal structure of the M 5 muscarinic acetylcholine receptor

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Binding Sites
  • Crystallization
  • Drug Design
  • Humans
  • Kinetics
  • Ligands
  • Models, Molecular
  • Protein Conformation
  • Receptor, Muscarinic M5 / chemistry*
  • Receptor, Muscarinic M5 / genetics
  • Receptor, Muscarinic M5 / metabolism*
  • Receptors, Muscarinic / chemistry
  • X-Ray Diffraction

Substances

  • Ligands
  • Receptor, Muscarinic M5
  • Receptors, Muscarinic

Associated data

  • PDB/6OL9