High-resolution structures of human Na v 1.7 reveal gating modulation through α-π helical transition of S6 IV

• Published in: Cell reports (Cambridge) Vol. 39; no. 4; p. 110735
• Main Authors: Huang, Gaoxingyu, Liu, Dongliang, Wang, Weipeng, Wu, Qiurong, Chen, Jiaofeng, Pan, Xiaojing, Shen, Huaizong, Yan, Nieng
• Format: Journal Article
• Language: English
• Published: United States 26-04-2022
• Subjects: Binding Sites; Humans; Ion Channel Gating; Protein Conformation, alpha-Helical; Protein Domains; Sodium Channels - metabolism; Nav1.7; pain; CP: Neuroscience; SCN9A; CP: Molecular biology; Huwentoxin IV; channel gating; π helix; Protoxin II; allosteric modulation; cryo-EM structures; fast inactivation
• ISSN: 2211-1247

Na
1.7 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
1.7 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
1.7(E406K) bound to various toxins identifies two distinct conformations of S6
, one composed of α helical turns only and the other containing a π helical turn in the middle. The structure of ligand-free Na
1.7(E406K), determined at 3.5-Å resolution, is identical to the WT channel, confirming that binding of Huwentoxin IV or Protoxin II to VSD
allosterically induces the α → π transition of S6
. 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.