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Title | High-resolution structures of human Na1.7 reveal gating modulation through α-π helical transition of S6. |
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Journal, issue, pages | Cell Rep, Vol. 39, Issue 4, Page 110735, Year 2022 |
Publish date | Apr 26, 2022 |
Authors | Gaoxingyu Huang / Dongliang Liu / Weipeng Wang / Qiurong Wu / Jiaofeng Chen / Xiaojing Pan / Huaizong Shen / Nieng Yan / |
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 ...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. |
External links | Cell Rep / PubMed:35476982 |
Methods | EM (single particle) |
Resolution | 2.2 - 3.5 Å |
Structure data | EMDB-32368, PDB-7w9k: EMDB-32369, PDB-7w9l: EMDB-32370, PDB-7w9m: EMDB-32371, PDB-7w9p: EMDB-32372, PDB-7w9t: |
Chemicals | ChemComp-NAG: ChemComp-P5S: ChemComp-Y01: ChemComp-9Z9: ChemComp-NA: ChemComp-LPE: ChemComp-1PW: ChemComp-PCW: ChemComp-HOH: ChemComp-9SR: ChemComp-9SL: |
Source |
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Keywords | MEMBRANE PROTEIN / Nav1.7 / SCN9A / cryo-EM / voltage gated sodium channel |