7W9T

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

Summary for 7W9T

• Entry DOI: 10.2210/pdb7w9t/pdb
• EMDB information: 32372
• Descriptor: Sodium channel protein type 9 subunit alpha, 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (11 entities in total)
• Functional Keywords: voltage gated sodium channel, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 298626.53

Authors

Yan, N.,Huang, G.,Liu, D.,Wei, P. (deposition date: 2021-12-10, release date: 2022-05-25, Last modification date: 2024-10-30)

Primary citation

Huang, G.,Liu, D.,Wang, W.,Wu, Q.,Chen, J.,Pan, X.,Shen, H.,Yan, N.
High-resolution structures of human Na v 1.7 reveal gating modulation through alpha-pi helical transition of S6 IV.
Cell Rep, 39:110735-110735, 2022

PubMed Abstract: Na1.7 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) Na1.7 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 Na1.7(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 Na1.7(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.

PubMed: 35476982
DOI: 10.1016/j.celrep.2022.110735

Experimental method

ELECTRON MICROSCOPY (3 Å)