Structural basis of α-scorpion toxin action on Na v channels

Science. 2019 Mar 22;363(6433):eaav8573. doi: 10.1126/science.aav8573. Epub 2019 Feb 7.

Abstract

Fast inactivation of voltage-gated sodium (Nav) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Nav channel alone and in complex with a lethal α-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a ~13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of α-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Nav channels.

Publication types

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

MeSH terms

  • Animals
  • Cockroaches
  • Cryoelectron Microscopy
  • Humans
  • Models, Molecular
  • NAV1.7 Voltage-Gated Sodium Channel / chemistry*
  • Protein Domains
  • Recombinant Fusion Proteins / chemistry
  • Scorpion Venoms / chemistry*
  • Scorpion Venoms / pharmacology*
  • Sodium Channel Blockers / chemistry*
  • Sodium Channel Blockers / pharmacology*

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • Recombinant Fusion Proteins
  • SCN9A protein, human
  • Scorpion Venoms
  • Sodium Channel Blockers