PT  - JOURNAL ARTICLE
AU  - Ziva Vuckovic
AU  - Patrick R. Gentry
AU  - Alice E. Berizzi
AU  - Kunio Hirata
AU  - Swapna Varghese
AU  - Geoff Thompson
AU  - Emma T. van der Westhuizen
AU  - Wessel A.C. Burger
AU  - Raphaёl Rahmani
AU  - Celine Valant
AU  - Christopher J. Langmead
AU  - Craig W. Lindsley
AU  - Jonathan Baell
AU  - Andrew B. Tobin
AU  - Patrick M. Sexton
AU  - Arthur Christopoulos
AU  - David M. Thal
TI  - Crystal structure of the M<sub>5</sub> muscarinic acetylcholine receptor
AID  - 10.1101/730622
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 730622
4099  - http://biorxiv.org/content/early/2019/08/14/730622.short
4100  - http://biorxiv.org/content/early/2019/08/14/730622.full
AB  - 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 five 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 mAChR further revealed the 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 ligands.Significance Statement The five subtypes of the muscarinic acetylcholine receptors (mAChRs) are expressed throughout the central and peripheral nervous system where they play a vital role in physiology and pathologies. Recently, the M5 mAChR subtype has emerged as an exciting drug target for the treatment of drug addiction. We have determined the atomic structure of the M5 mAChR bound to the clinically used inverse agonist tiotropium. The M5 mAChR structure now allows for a full comparison of all five mAChR subtypes and reveals subtle differences in the extracellular loop (ECL) regions of the receptor that mediate orthosteric and allosteric ligand selectivity. Together these findings open the door for future structure-based design of selective drugs that target this therapeutically important class of receptors.