Molecular basis for ligand activation of the human KCNQ2 channel
Molecular basis for ligand activation of the human KCNQ2 channel
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DOI：
10.1038/s41422-020-00410-8
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发表时间：
2020-09-03
期刊：
影响因子：
44.1
通讯作者：
Guo, Jiangtao
中科院分区：
文献类型：
--
作者：
Li, Xiaoxiao;Zhang, Qiansen;Guo, Jiangtao
电压门控性钾通道KCNQ2负责神经元的M电流，是治疗癫痫、疼痛和其他与神经元过度兴奋相关的疾病的重要药物靶点。已经开发了一系列合成化合物来直接激活KCNQ2，但由于缺乏高分辨结构，我们对其激活机制的了解有限。在此，我们报道了人KCNQ2在apo状态和与两种激活剂ztz240或retigabine通过不同机制激活KCNQ2的复合体中的冷冻电子显微镜(Cryo-EM)结构。激活剂结合的结构和电生理分析表明，ztz240结合在电压敏感区域并直接将其稳定在激活状态，而瑞替加宾结合在孔域并通过变构调节激活通道。通过准确定义配体结合部位，这些KCNQ2结构不仅揭示了不同的配体识别和激活机制，而且为药物的优化和设计提供了结构基础。
The voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy, pain and several other diseases related to neuronal hyper-excitability. A list of synthetic compounds have been developed to directly activate KCNQ2, yet our knowledge of their activation mechanism is limited, due to lack of high-resolution structures. Here, we report cryo-electron microscopy (cryo-EM) structures of the human KCNQ2 determined in apo state and in complex with two activators, ztz240 or retigabine, which activate KCNQ2 through different mechanisms. The activator-bound structures, along with electrophysiology analysis, reveal that ztz240 binds at the voltage-sensing domain and directly stabilizes it at the activated state, whereas retigabine binds at the pore domain and activates the channel by an allosteric modulation. By accurately defining ligand-binding sites, these KCNQ2 structures not only reveal different ligand recognition and activation mechanisms, but also provide a structural basis for drug optimization and design.