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-Structure paper
| タイトル | Diverse binding poses of agonistic neurotoxins on human Na1.6. |
|---|---|
| ジャーナル・号・ページ | Nature, Year 2026 |
| 掲載日 | 2026年6月10日 |
著者 | Xiao Fan / Jian Huang / Lin Yang / Jiaofeng Chen / Huan Wang / Xiaoshuang Huang / Jinli Geng / Qinglin Wu / Yuzhen Xie / Fangzhou Lu / Qinmeng Guo / Zilin Shen / Xueqin Jin / Nieng Yan / ![]() |
| PubMed 要旨 | Voltage-gated sodium (Na) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional ...Voltage-gated sodium (Na) channels are key targets of various venomous toxins. Deciphering the binding poses and mechanisms of action of representative toxins will help to dissect the functional mechanism of the channels and facilitate therapeutic development targeting Na channels. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Na1.6-β1 channel complex. The globular β-scorpion toxin Cn2 nestles between the extracellular segment of voltage-sensing domain (VSD) in the second repeat of the Na1.6 core α-unit (VSD) and the pore extracellular loops in the third repeat of the Na1.6 core α-unit (ECL), where it is stabilized by interactions with both protein regions and the branched N1372-glycan. Cone snail ι-conotoxin RXIA adopts an elongated conformation, spanning VSD and VSD to wrap around the shoulder of the pore domain (PD). The bullet ant-derived toxin δ-paraponeritoxin-Pc1a exists as a transmembrane helix that stands between VSD and PD. Our findings, corroborated by functional characterizations, illustrate the diversity in peptide toxin binding poses and mechanisms of action, link stabilization of the up state of VSD or VSD to channel activation, and provide clues to the rational design of selective Na channel modulators. |
リンク | Nature / PubMed:42271061 |
| 手法 | EM (単粒子) |
| 解像度 | 2.5 - 3.1 Å |
| 構造データ | EMDB-80133, PDB-25ih: EMDB-80134, PDB-25ii: EMDB-80135, PDB-25ij: |
| 化合物 | ![]() ChemComp-NAG: ![]() ChemComp-9Z9: ![]() ChemComp-PCW: ![]() ChemComp-Y01: ![]() ChemComp-CLR: ![]() ChemComp-P5S: ![]() ChemComp-LPE: ![]() ChemComp-P3X: ![]() ChemComp-PT5: ![]() ChemComp-HOH: ![]() ChemComp-NA: |
| 由来 |
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キーワード | MEMBRANE PROTEIN / Nav1.6 / voltage gated sodium channel / cryo-EM / toxin / Cn2 / TRANSPORT PROTEIN-TOXIN complex / Iota-Conotoxin RXIA / Pc1a / delta-paraponeritoxin-Pc1a / TRANSPORT PROTEIN |
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homo sapiens (ヒト)
conus radiatus (クリイロイモ)
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