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

Nat Commun. 2021 Jan 4;12(1):128. doi: 10.1038/s41467-020-20078-3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / drug effects
  • Molecular Dynamics Simulation
  • 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
  • Scorpion Venoms / chemistry
  • Scorpion Venoms / toxicity*
  • Sodium / metabolism

Substances

  • NAV1.5 Voltage-Gated Sodium Channel
  • Scorpion Venoms
  • Sodium