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

ABSTRACT: Voltage-gated sodium (Na_V) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The ?-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na_V1.5 channels with IC₅₀?=?11.4?nM. Here we reveal the structure of LqhIII bound to Na_V1.5 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.

SUBMITTER: Jiang D 

PROVIDER: S-EPMC7782738 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature