%0 Journal Article
%T High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV.
%A Huang G
%A Liu D
%A Wang W
%A Wu Q
%A Chen J
%A Pan X
%A Shen H
%A Yan N
%J Cell Rep
%V 39
%N 4
%D 04 2022 26
%M 35476982
暂无%R 10.1016/j.celrep.2022.110735
%X 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.