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

Voltage-gated sodium (Na-V) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The alpha -toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na(V)1.5 channels with IC50=11.4nM. Here we reveal the structure of LqhIII bound to Na(V)1.5 at 3.3 angstrom 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 alpha -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.

Automated summary

The alpha-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na(V)1.5 channels. The cryo-EM structure of LqhIII bound to Na(V)1.5 shows that it traps the gating charges of the S4 segment in a unique intermediate-activated state, explaining why LqhIII slows inactivation of Na-V channels but does not open them.