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Nature. 2016 Mar 17;531(7594):335-40. doi: 10.1038/nature17188. Epub 2016 Mar 9.

Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.

Author information

1
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia.
2
ConfometRx, 3070 Kenneth Street, Santa Clara, California 95054, USA.
3
Neuroscience, Eli Lilly, Indianapolis, Indiana 46285, USA.
4
Computational Chemistry and Chemoinformatics, Eli Lilly, Indianapolis, Indiana 46285, USA.
5
Computational Chemistry and Chemoinformatics, Eli Lilly, Sunninghill Road, Windlesham GU20 6PH, UK.
6
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
7
Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.

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.

PMID:
26958838
PMCID:
PMC4915387
DOI:
10.1038/nature17188
[Indexed for MEDLINE]
Free PMC Article

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