Structures of human Na v 1.7 channel in complex with auxiliary subunits and animal toxins

Science. 2019 Mar 22;363(6433):1303-1308. doi: 10.1126/science.aaw2493. Epub 2019 Feb 14.

Abstract

Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief. Here we report the cryo-electron microscopy structures of the human Nav1.7-β1-β2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The two structures are nearly identical except for minor shifts of voltage-sensing domain II (VSDII), whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in VSDIV The structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Nav1.7 and establish the foundation for structure-aided development of analgesics.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Humans
  • NAV1.7 Voltage-Gated Sodium Channel / chemistry*
  • Peptides / chemistry*
  • Protein Conformation
  • Saxitoxin / chemistry*
  • Spider Venoms / chemistry*
  • Tetrodotoxin / chemistry*
  • Voltage-Gated Sodium Channel Blockers / chemistry*
  • Voltage-Gated Sodium Channel beta-1 Subunit / chemistry*
  • Voltage-Gated Sodium Channel beta-2 Subunit / chemistry*

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • Peptides
  • SCN1B protein, human
  • SCN2B protein, human
  • SCN9A protein, human
  • Spider Venoms
  • Voltage-Gated Sodium Channel Blockers
  • Voltage-Gated Sodium Channel beta-1 Subunit
  • Voltage-Gated Sodium Channel beta-2 Subunit
  • huwentoxin IV, Selenocosmia huwena
  • protoxin II, Thrixopelma pruriens
  • Saxitoxin
  • Tetrodotoxin