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

• Published in: Nature communications Vol. 12; no. 1; pp. 128 - 13
• Main Authors: Jiang, Daohua, Tonggu, Lige, Gamal El-Din, Tamer M., Banh, Richard, Pomès, Régis, Zheng, Ning, Catterall, William A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/45/535/1258/1259; 631/57/2270; Animals; Binding; Binding Sites; Channel gating; Channels; Cryoelectron Microscopy; Deactivation; Heart; HEK293 Cells; Humanities and Social Sciences; Humans; Inactivation; Ion Channel Gating - drug effects; Molecular Dynamics Simulation; multidisciplinary; Myocardium - metabolism; NAV1.5 Voltage-Gated Sodium Channel - chemistry; NAV1.5 Voltage-Gated Sodium Channel - metabolism; NAV1.5 Voltage-Gated Sodium Channel - ultrastructure; Protein Conformation; Rats; Science; Science (multidisciplinary); Scorpion Venoms - chemistry; Scorpion Venoms - toxicity; Segments; Sensors; Sodium; Sodium - metabolism; Sodium channels (voltage-gated); Toxins; Trapping; Traps; α-Toxin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20078-3

Voltage-gated sodium (Na V ) 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 Na V 1.5 channels with IC 50  = 11.4 nM. Here we reveal the structure of LqhIII bound to Na V 1.5 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 Na V 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 Na V channels. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na V 1.5 channels. Here authors reveal the cryo-EM structure of LqhIII bound to Na V 1.5 which shows that LqhIII traps the gating charges of the S4 segment in a unique intermediate-activated state and explains why LqhIII slows inactivation of Na V channels but does not open them.