High-resolution structures of human Na_v1.7 reveal gating modulation through α-π helical transition of S6_IV

Na_v1.7 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) Na_v1.7 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 Na_v1.7(E406K) bound to various toxins identifies two distinct conformations of S6_IV, one composed of α helical turns only and the other containing a π helical turn in the middle. The structure of ligand-free Na_v1.7(E406K), determined at 3.5-Å resolution, is identical to the WT channel, confirming that binding of Huwentoxin IV or Protoxin II to VSD_II allosterically induces the α → π transition of S6_IV. 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.