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Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin

Author

Listed:
  • Yue Li

    (Institute of Biophysics, Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Tian Yuan

    (Peking University Health Science Center
    Peking University)

  • Bo Huang

    (Beijing StoneWise Technology Co Ltd.)

  • Feng Zhou

    (Beijing StoneWise Technology Co Ltd.)

  • Chao Peng

    (Peking University Health Science Center
    Peking University)

  • Xiaojing Li

    (Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yunlong Qiu

    (Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Bei Yang

    (Institute of Biophysics, Chinese Academy of Sciences)

  • Yan Zhao

    (Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhuo Huang

    (Peking University Health Science Center
    Peking University)

  • Daohua Jiang

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

Abstract

The sodium channel NaV1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of NaV1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human NaV1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of NaV1.6 inhibition by the blocker. The apo-form structure reveals two potential Na+ binding sites within the selectivity filter, suggesting a possible mechanism for Na+ selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na+ binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into NaV1.6 structure, ion conductance, and inhibition.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36766-9
    DOI: 10.1038/s41467-023-36766-9
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    References listed on IDEAS

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    1. 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.
    2. Jian Payandeh & Todd Scheuer & Ning Zheng & William A. Catterall, 2011. "The crystal structure of a voltage-gated sodium channel," Nature, Nature, vol. 475(7356), pages 353-358, July.
    3. Lin Tang & Tamer M. Gamal El-Din & Jian Payandeh & Gilbert Q. Martinez & Teresa M. Heard & Todd Scheuer & Ning Zheng & William A. Catterall, 2014. "Structural basis for Ca2+ selectivity of a voltage-gated calcium channel," Nature, Nature, vol. 505(7481), pages 56-61, January.
    4. 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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    1. Huiwen Chen & Zhanyi Xia & Jie Dong & Bo Huang & Jiangtao Zhang & Feng Zhou & Rui Yan & Yiqiang Shi & Jianke Gong & Juquan Jiang & Zhuo Huang & Daohua Jiang, 2024. "Structural mechanism of voltage-gated sodium channel slow inactivation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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