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Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin

Author

Listed:
  • Daohua Jiang

    (University of Washington)

  • Lige Tonggu

    (University of Washington)

  • Tamer M. Gamal El-Din

    (University of Washington)

  • Richard Banh

    (Molecular Medicine, Hospital for Sick Children
    University of Toronto)

  • Régis Pomès

    (Molecular Medicine, Hospital for Sick Children
    University of Toronto)

  • Ning Zheng

    (University of Washington
    Howard Hughes Medical Institute, University of Washington)

  • William A. Catterall

    (University of Washington)

Abstract

Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50 = 11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20078-3
    DOI: 10.1038/s41467-020-20078-3
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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. 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.
    3. 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.
    4. Rían W. Manville & J. Alfredo Freites & Richard Sidlow & Douglas J. Tobias & Geoffrey W. Abbott, 2023. "Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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