近日，西湖生命科学与生物医学实验室教授卢培龙及其小组报道了从头设计的电压门控阴离子通道抑制神经元放电。2025年10月16日出版的《细胞》发表了这项成果。
小组报道了电压门控阴离子通道即dVGACs的精确从头设计。在膜片钳实验中，dVGACs采用15螺旋五聚体结构，在跨膜范围内存在精氨酸收缩，并显示出电压依赖的阴离子电流。低温电子显微镜（cryo-EM）显示，dVGACs的结构与设计模型非常吻合。低温电镜结构和分子动力学模拟表明，精氨酸收缩体经历电压诱导的构象变化，既可以作为电压传感器，又可以作为选择性滤波器。值得注意的是，dVGACs的阴离子选择性和电压敏感性可以通过靶向突变来原位抑制神经元放电。通过他们设计的构象变化来创建离子通道的能力刷新了他们对膜生物物理学的见解，并揭示了各种潜在的应用。
据悉，设计响应环境信号的离子通道对调节细胞活动和传感器的发展具有重要意义，但由于设计刺激诱导的蛋白质构象变化的复杂性，它仍然是一个重大挑战。
附：英文原文
Title: De novo designed voltage-gated anion channels suppress neuron firing
Author: Chen Zhou, Huican Li, Jiaxing Wang, Cheng Qian, Hui Xiong, Zhilin Chu, Qiming Shao, Xuan Li, Shijin Sun, Ke Sun, Aiqin Zhu, Jiawei Wang, Xueqin Jin, Fan Yang, Tamer M. Gamal El-Din, Bo Li, Jing Huang, Kun Wu, Peilong Lu
Issue&Volume: 2025-10-16
Abstract: Design of ion channels responsive to environmental cues has significant implications in modulating cellular activities and sensor development, but it remains a significant challenge due to the complexities involved in designing stimuli-induced conformational changes in proteins. Here, we report the accurate de novo design of voltage-gated anion channels, namely dVGACs. dVGACs adopt a 15-helix pentameric architecture featuring arginine constrictions within the transmembrane span and show voltage-dependent anions currents in patch-clamp experiments. Cryo-electron microscopy (cryo-EM) structures of dVGACs closely align with the design models. Cryo-EM structures and molecular dynamics simulations suggest that the arginine constrictions undergo voltage-induced conformational changes, serving as both a voltage sensor and a selectivity filter as designed. Notably, the anion selectivity and voltage sensitivity of dVGACs can be tuned through targeted mutations for suppressing neuronal firing in situ. The ability to create ion channels with custom-designed conformational changes refreshes our insights into membrane biophysics and unveils diverse potential applications.
DOI: 10.1016/j.cell.2025.09.023
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01091-8