Crystal structures of the M1 and M4 muscarinic acetylcholine receptors

David M. Thal, Bingfa Sun, Dan Feng, Vindhya Nawaratne, Katie Leach, Christian C. Felder, Mark G. Bures, David A. Evans, William I. Weis, Priti Bachhawat, Tong Sun Kobilka, Patrick M. Sexton (), Brian K. Kobilka () and Arthur Christopoulos ()
Additional contact information
David M. Thal: Monash Institute of Pharmaceutical Sciences, Monash University
Bingfa Sun: ConfometRx
Dan Feng: ConfometRx
Vindhya Nawaratne: Monash Institute of Pharmaceutical Sciences, Monash University
Katie Leach: Monash Institute of Pharmaceutical Sciences, Monash University
Christian C. Felder: Neuroscience
Mark G. Bures: Computational Chemistry and Chemoinformatics
David A. Evans: Computational Chemistry and Chemoinformatics
William I. Weis: Stanford University School of Medicine
Priti Bachhawat: ConfometRx
Tong Sun Kobilka: ConfometRx
Patrick M. Sexton: Monash Institute of Pharmaceutical Sciences, Monash University
Brian K. Kobilka: ConfometRx
Arthur Christopoulos: Monash Institute of Pharmaceutical Sciences, Monash University

Nature, 2016, vol. 531, issue 7594, 335-340

Abstract: Abstract Muscarinic M1–M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer’s disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.

Date: 2016
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DOI: 10.1038/nature17188

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