激动性神经毒素在人Nav 1.6上的不同结合方式
激动性神经毒素在人Nav1.6上的不同结合方式
作者： 小柯机器人 发布时间：2026/6/11 17:08:34
本期文章：《自然》：Online/在线发表
深圳医学科学院颜宁团队宣布他们的研究揭示激动性神经毒素在人Nav1.6上的不同结合方式。2026年6月10日出版的《自然》发表了这项成果。
在这里，课题组展示了三种激动肽毒素在人Nav1.6 -β1通道复合物上不同结合姿态的冷冻电镜（cryo-EM）结构。球形β-蝎子毒素Cn2位于Nav1.6核心α-单元（VSDII）的第二重复的电压感应结构域（VSD）的胞外段和Nav1.6核心α-单元（ECLIII）的第三重复的孔胞外环之间，通过与蛋白质区域和支链n1372 -聚糖相互作用而稳定。锥螺毒素RXIA采用细长的构象，跨越VSDI和VSDIV，包裹在孔域（PD）肩部。子弹蚁衍生的毒素δ-副鹅膏毒素-Pc1a以跨膜螺旋的形式存在于VSDII和PDIII之间。他们的研究结果得到了功能表征的证实，阐明了肽毒素结合姿势和作用机制的多样性，将VSDI或VSDII上状态的稳定与通道激活联系起来，并为选择性Nav通道调节剂的合理设计提供了线索。
据介绍，电压门控钠（Nav）通道是各种毒蛇毒素的关键靶点。破译代表性毒素的结合姿势和作用机制将有助于解剖这些通道的功能机制，并促进针对Nav通道的治疗开发。
附：英文原文
Title: Diverse binding poses of agonistic neurotoxins on human Nav1.6
Author: Fan, Xiao, Huang, Jian, Yang, Lin, Chen, Jiaofeng, Wang, Huan, Huang, Xiaoshuang, Geng, Jinli, Wu, Qinglin, Xie, Yuzhen, Lu, Fangzhou, Guo, Qinmeng, Shen, Zilin, Jin, Xueqin, Yan, Nieng
Issue&Volume: 2026-06-10
Abstract: Voltage-gated sodium (Nav) 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 Nav channels1,2. Here we present cryo-electron microscopy (cryo-EM) structures of distinct binding poses of three agonistic peptide toxins on the human Nav1.6–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 Nav1.6 core α-unit (VSDII) and the pore extracellular loops in the third repeat of the Nav1.6 core α-unit (ECLIII), 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 VSDI and VSDIV 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 VSDII and PDIII. 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 VSDI or VSDII to channel activation, and provide clues to the rational design of selective Nav channel modulators.
DOI: 10.1038/s41586-026-10661-x
Source: https://www.nature.com/articles/s41586-026-10661-x