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Updated: Sep 25, 2025

Site Directed Spin Labeling and EPR Spectroscopic Studies of Pentameric Ligand-Gated Ion Channels
Published on: July 4, 2016
High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV
Gaoxingyu Huang1, Dongliang Liu1, Weipeng Wang2
1Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, Zhejiang Province 310024, China; Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou, Zhejiang Province 310024, China.
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.
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