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The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands

Author

Listed:
  • Jingjing Wang

    (ShanghaiTech University)

  • Meng Wu

    (ShanghaiTech University)

  • Zhangcheng Chen

    (Chinese Academy of Sciences)

  • Lijie Wu

    (ShanghaiTech University)

  • Tian Wang

    (ShanghaiTech University
    ShanghaiTech University)

  • Dongmei Cao

    (Chinese Academy of Sciences)

  • Huan Wang

    (ShanghaiTech University)

  • Shenhui Liu

    (ShanghaiTech University
    ShanghaiTech University)

  • Yueming Xu

    (ShanghaiTech University)

  • Fei Li

    (ShanghaiTech University)

  • Junlin Liu

    (ShanghaiTech University)

  • Na Chen

    (ShanghaiTech University)

  • Suwen Zhao

    (ShanghaiTech University
    ShanghaiTech University)

  • Jianjun Cheng

    (ShanghaiTech University)

  • Sheng Wang

    (Chinese Academy of Sciences)

  • Tian Hua

    (ShanghaiTech University
    ShanghaiTech University)

Abstract

Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer’s disease and schizophrenia. However, the lack of understanding on M4R’s activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-Gi structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30595-y
    DOI: 10.1038/s41467-022-30595-y
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    References listed on IDEAS

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    3. Antoine Koehl & Hongli Hu & Shoji Maeda & Yan Zhang & Qianhui Qu & Joseph M. Paggi & Naomi R. Latorraca & Daniel Hilger & Roger Dawson & Hugues Matile & Gebhard F. X. Schertler & Sebastien Granier & W, 2018. "Structure of the µ-opioid receptor–Gi protein complex," Nature, Nature, vol. 558(7711), pages 547-552, June.
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    1. 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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