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

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

Journal, date & volume: Cell Rep, 2022Apr26, 39, 110735

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/35476982

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.