High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV

Gaoxingyu Huang, Dongliang Liu, Weipeng Wang, Qiurong Wu, Jiaofeng Chen, Xiaojing Pan, Huaizong Shen, Nieng Yan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Nav1.7 represents a preeminent target for next-generation analgesics for its critical role in pain sensation. Here we report a 2.2-Å resolution cryo-EM structure of wild-type (WT) Nav1.7 complexed with the β1 and β2 subunits that reveals several previously indiscernible cytosolic segments. Reprocessing of the cryo-EM data for our reported structures of Nav1.7(E406K) bound to various toxins identifies two distinct conformations of S6IV, one composed of α helical turns only and the other containing a π helical turn in the middle. The structure of ligand-free Nav1.7(E406K), determined at 3.5-Å resolution, is identical to the WT channel, confirming that binding of Huwentoxin IV or Protoxin II to VSDII allosterically induces the α → π transition of S6IV. The local secondary structural shift leads to contraction of the intracellular gate, closure of the fenestration on the interface of repeats I and IV, and rearrangement of the binding site for the fast inactivation motif.

Original languageEnglish (US)
Article number110735
JournalCell Reports
Volume39
Issue number4
DOIs
StatePublished - Apr 26 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • CP: Molecular biology
  • CP: Neuroscience
  • Huwentoxin IV
  • Nav1.7
  • Protoxin II
  • SCN9A
  • allosteric modulation
  • channel gating
  • cryo-EM structures
  • fast inactivation
  • pain
  • π helix

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