{Reference Type}: Journal Article
{Title}: High-resolution structures of human Nav1.7 reveal gating modulation through α-π helical transition of S6IV.
{Author}: Huang G;Liu D;Wang W;Wu Q;Chen J;Pan X;Shen H;Yan N;
{Journal}: Cell Rep
{Volume}: 39
{Issue}: 4
{Year}: 04 2022 26
暂无{DOI}: 10.1016/j.celrep.2022.110735
{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.