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

Daohua Jiang, Lige Tonggu, Tamer M. Gamal El-Din, Richard Banh, Régis Pomès, Ning Zheng () and William A. Catterall ()
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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
Régis Pomès: Molecular Medicine, Hospital for Sick Children
Ning Zheng: University of Washington
William A. Catterall: University of Washington

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20078-3

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