小柯机器人

普林斯顿大学颜宁、北京大学宋晨和武汉大学高帅小组揭示了人Ca_v1.2受多种药物和神经毒素calciseptine抑制的结构基础。相关论文于2023年11月15日发表于国际学术期刊《细胞》杂志。

研究人员解析了人Ca_v1.2的冷冻电镜结构，包括其自身形式和与多种药物以及多肽神经毒素calciseptine的复合物。大多数结构，无论是无活性结构还是与calciseptine、氨氯地平或胺碘酮和索非布韦复合物结合的结构，都表现出一致的失活构象，其具有一个密封的栅极、三个向上的电压感应结构域（VSD）和一个向下的VSD_II。calciseptine位于孔结构域的肩部，远离渗透路径。

与此相反，将解痉药物匹维溴铵置入类似于Na_v通道中的IFM结合位点空腔时，会发生一系列结构变化，包括VSD_II上移，选择性过滤及重复III周围片段的扩张。与此同时，S4-5_III与S5_III合并成一个螺旋，从而形成一个加宽但仍不导电的胞内门。

据悉，Ca_v1.2通道在各种神经元和生理过程中发挥至关重要的作用。

附：英文原文

Title: Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine

Author: Shuai Gao, Xia Yao, Jiaofeng Chen, Gaoxingyu Huang, Xiao Fan, Lingfeng Xue, Zhangqiang Li, Tong Wu, Yupeng Zheng, Jian Huang, Xueqin Jin, Yan Wang, Zhifei Wang, Yong Yu, Lei Liu, Xiaojing Pan, Chen Song, Nieng Yan

Issue&Volume: 2023-11-15

Abstract: Cav1.2 channels play crucial roles in various neuronal and physiological processes. Here,we present cryo-EM structures of human Cav1.2, both in its apo form and in complex with several drugs, as well as the peptideneurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine,or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformationwith a sealed gate, three up voltage-sensing domains (VSDs), and a down VSDII. Calciseptine sits on the shoulder of the pore domain, away from the permeation path.In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavityreminiscent of the IFM-binding site in Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeatIII. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellulargate.

DOI: 10.1016/j.cell.2023.10.007

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01106-6