Structural Basis for the Modulation of Voltage-Gated Sodium Channels by Animal Toxins

Science. 2018 Oct 19;362(6412):eaau2596. doi: 10.1126/science.aau2596. Epub 2018 Jul 26.

Abstract

Animal toxins that modulate the activity of voltage-gated sodium (Nav) channels are broadly divided into two categories-pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Nav channel NavPaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSDII and the pore of NavPaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na+ access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Nav channel drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cryoelectron Microscopy
  • Insect Proteins / antagonists & inhibitors*
  • Insect Proteins / chemistry*
  • Insect Proteins / ultrastructure
  • Ion Channel Gating / drug effects
  • Periplaneta
  • Protein Domains
  • Saxitoxin / chemistry
  • Spider Venoms / chemistry*
  • Tetrodotoxin / chemistry
  • Voltage-Gated Sodium Channel Blockers / chemistry*
  • Voltage-Gated Sodium Channels / chemistry*
  • Voltage-Gated Sodium Channels / ultrastructure

Substances

  • Insect Proteins
  • Spider Venoms
  • Voltage-Gated Sodium Channel Blockers
  • Voltage-Gated Sodium Channels
  • Saxitoxin
  • Tetrodotoxin