EMD-32372

Single-particle
3.0 Å
EMD-32372 Deposition: 10/12/2021
Map released: 25/05/2022
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
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EMD-32372

Cryo-EM structure of human Nav1.7(E406K) in complex with auxiliary beta subunits, huwentoxin-IV and saxitoxin (S6IV alpha helix conformer)

EMD-32372

Single-particle
3.0 Å
EMD-32372 Deposition: 10/12/2021
Map released: 25/05/2022
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: human Nav1.7 in complex with beta1, beta2 and Huwentoxin
Fitted models: 7w9t (Avg. Q-score: 0.431)

Deposition Authors: Yan N, Huang G, Liu D, Wei P
High-resolution structures of human Na v 1.7 reveal gating modulation through alpha-pi helical transition of S6 IV.
Huang G, Liu D, Wang W, Wu Q, Chen J, Pan X , Shen H, Yan N
(2022) Cell Rep , 39 , 110735 - 110735
PUBMED: 35476982
DOI: doi:10.1016/j.celrep.2022.110735
ISSN: 2211-1247
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.