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Ligand activation mechanisms of human KCNQ2 channel

Author

Listed:
  • Demin Ma

    (Zhejiang University School of Medicine
    Nanhu Brain-computer Interface Institute)

  • Yueming Zheng

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xiaoxiao Li

    (Zhejiang University School of Medicine
    Nanhu Brain-computer Interface Institute)

  • Xiaoyu Zhou

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhenni Yang

    (Zhejiang University School of Medicine
    Nanhu Brain-computer Interface Institute)

  • Yan Zhang

    (Zhejiang University School of Medicine
    Nanhu Brain-computer Interface Institute)

  • Long Wang

    (Chinese Academy of Sciences)

  • Wenbo Zhang

    (Chinese Academy of Sciences)

  • Jiajia Fang

    (Zhejiang University School of Medicine)

  • Guohua Zhao

    (Zhejiang University School of Medicine)

  • Panpan Hou

    (Macau University of Science and Technology)

  • Fajun Nan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wei Yang

    (Zhejiang University School of Medicine)

  • Nannan Su

    (Zhejiang University School of Medicine)

  • Zhaobing Gao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Jiangtao Guo

    (Zhejiang University School of Medicine
    Nanhu Brain-computer Interface Institute
    Zhejiang University School of Medicine
    Zhejiang University Medical Center)

Abstract

The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP2), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP2, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2.

Suggested Citation

  • Demin Ma & Yueming Zheng & Xiaoxiao Li & Xiaoyu Zhou & Zhenni Yang & Yan Zhang & Long Wang & Wenbo Zhang & Jiajia Fang & Guohua Zhao & Panpan Hou & Fajun Nan & Wei Yang & Nannan Su & Zhaobing Gao & Ji, 2023. "Ligand activation mechanisms of human KCNQ2 channel," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42416-x
    DOI: 10.1038/s41467-023-42416-x
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    References listed on IDEAS

    as
    1. Jian Huang & Xiao Fan & Xueqin Jin & Sooyeon Jo & Hanxiong Bear Zhang & Akie Fujita & Bruce P. Bean & Nieng Yan, 2023. "Cannabidiol inhibits Nav channels through two distinct binding sites," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. Ruth A. Pumroy & Anna D. Protopopova & Tabea C. Fricke & Iris U. Lange & Ferdinand M. Haug & Phuong T. Nguyen & Pamela N. Gallo & Bárbara B. Sousa & Gonçalo J. L. Bernardes & Vladimir Yarov-Yarovoy & , 2022. "Structural insights into TRPV2 activation by small molecules," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Katrien Willegems & Jodene Eldstrom & Efthimios Kyriakis & Fariba Ataei & Harutyun Sahakyan & Ying Dou & Sophia Russo & Filip Petegem & David Fedida, 2022. "Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
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