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Crystal structures of the M1 and M4 muscarinic acetylcholine receptors

Author

Listed:
  • 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
    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
    Stanford University School of Medicine)

  • Arthur Christopoulos

    (Monash Institute of Pharmaceutical Sciences, Monash University)

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.

Suggested Citation

  • 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. Sexto, 2016. "Crystal structures of the M1 and M4 muscarinic acetylcholine receptors," Nature, Nature, vol. 531(7594), pages 335-340, March.
  • Handle: RePEc:nat:nature:v:531:y:2016:i:7594:d:10.1038_nature17188
    DOI: 10.1038/nature17188
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    Cited by:

    1. Xueqian Peng & Linlin Yang & Zixuan Liu & Siyi Lou & Shiliu Mei & Meiling Li & Zhong Chen & Haitao Zhang, 2022. "Structural basis for recognition of antihistamine drug by human histamine receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Jingjing Wang & Meng Wu & Zhangcheng Chen & Lijie Wu & Tian Wang & Dongmei Cao & Huan Wang & Shenhui Liu & Yueming Xu & Fei Li & Junlin Liu & Na Chen & Suwen Zhao & Jianjun Cheng & Sheng Wang & Tian H, 2022. "The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Jinkang Shen & Dongqi Zhang & Yao Fu & Anqi Chen & Xiaoli Yang & Haitao Zhang, 2022. "Cryo-EM structures of human bradykinin receptor-Gq proteins complexes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Wessel A. C. Burger & Vi Pham & Ziva Vuckovic & Alexander S. Powers & Jesse I. Mobbs & Yianni Laloudakis & Alisa Glukhova & Denise Wootten & Andrew B. Tobin & Patrick M. Sexton & Steven M. Paul & Chri, 2023. "Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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