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Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist

Author

Listed:
  • Xiaojing Li

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

  • Feng Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions
    University of Copenhagen)

  • Hao Xu

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Shuli Zhang

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

  • Yiwei Gao

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

  • Hongwei Zhang

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

  • Yanli Dong

    (Chinese Academy of Sciences)

  • Yanchun Zheng

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

  • Bei Yang

    (Chinese Academy of Sciences)

  • Jianyuan Sun

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions)

  • Xuejun Cai Zhang

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

  • Yan Zhao

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

  • Daohua Jiang

    (Chinese Academy of Sciences)

Abstract

Voltage-gated sodium (NaV) channels play fundamental roles in initiating and propagating action potentials. NaV1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human NaV1.3/β1/β2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of NaV channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on NaV channels and pave a way for subtype-selective therapeutic development.

Suggested Citation

  • Xiaojing Li & Feng Xu & Hao Xu & Shuli Zhang & Yiwei Gao & Hongwei Zhang & Yanli Dong & Yanchun Zheng & Bei Yang & Jianyuan Sun & Xuejun Cai Zhang & Yan Zhao & Daohua Jiang, 2022. "Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28808-5
    DOI: 10.1038/s41467-022-28808-5
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    References listed on IDEAS

    as
    1. Daohua Jiang & Lige Tonggu & Tamer M. Gamal El-Din & Richard Banh & Régis Pomès & Ning Zheng & William A. Catterall, 2021. "Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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    Cited by:

    1. Yue Li & Tian Yuan & Bo Huang & Feng Zhou & Chao Peng & Xiaojing Li & Yunlong Qiu & Bei Yang & Yan Zhao & Zhuo Huang & Daohua Jiang, 2023. "Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Qiansheng Liang & Gamma Chi & Leonardo Cirqueira & Lianteng Zhi & Agostino Marasco & Nadia Pilati & Martin J. Gunthorpe & Giuseppe Alvaro & Charles H. Large & David B. Sauer & Werner Treptow & Manuel , 2024. "The binding and mechanism of a positive allosteric modulator of Kv3 channels," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Qiurong Wu & Jian Huang & Xiao Fan & Kan Wang & Xueqin Jin & Gaoxingyu Huang & Jiaao Li & Xiaojing Pan & Nieng Yan, 2023. "Structural mapping of Nav1.7 antagonists," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Lige Tonggu & Goragot Wisedchaisri & Tamer M. Gamal El-Din & Michael J. Lenaeus & Matthew M. Logan & Tatsuya Toma & Justin Bois & Ning Zheng & William A. Catterall, 2024. "Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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