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, Arthur Christopoulos

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)335-340
Number of pages6
JournalNature
Volume531
Issue number7594
DOIs
Publication statusPublished - 17 Mar 2016

Cite this

Thal, David M. ; Sun, Bingfa ; Feng, Dan ; Nawaratne, Vindhya ; Leach, Katie ; Felder, Christian C ; Bures, Mark G ; Evans, David A ; Weis, William I ; Bachhawat, Priti ; Kobilka, Tong Sun ; Sexton, Patrick M ; Kobilka, Brian K ; Christopoulos, Arthur. / Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. In: Nature. 2016 ; Vol. 531, No. 7594. pp. 335-340.
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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.",
author = "Thal, {David M.} and Bingfa Sun and Dan Feng and Vindhya Nawaratne and Katie Leach and Felder, {Christian C} and Bures, {Mark G} and Evans, {David A} and Weis, {William I} and Priti Bachhawat and Kobilka, {Tong Sun} and Sexton, {Patrick M} and Kobilka, {Brian K} and Arthur Christopoulos",
year = "2016",
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day = "17",
doi = "10.1038/nature17188",
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Thal, DM, Sun, B, Feng, D, Nawaratne, V, Leach, K, Felder, CC, Bures, MG, Evans, DA, Weis, WI, Bachhawat, P, Kobilka, TS, Sexton, PM, Kobilka, BK & Christopoulos, A 2016, 'Crystal structures of the M1 and M4 muscarinic acetylcholine receptors', Nature, vol. 531, no. 7594, pp. 335-340. https://doi.org/10.1038/nature17188

Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. / Thal, David M.; Sun, Bingfa; Feng, Dan; Nawaratne, Vindhya; Leach, Katie; Felder, Christian C; Bures, Mark G; Evans, David A; Weis, William I; Bachhawat, Priti; Kobilka, Tong Sun; Sexton, Patrick M; Kobilka, Brian K; Christopoulos, Arthur.

In: Nature, Vol. 531, No. 7594, 17.03.2016, p. 335-340.

Research output: Contribution to journalArticleResearchpeer-review

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