axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / ankyrin binding / voltage-gated potassium channel activity / potassium ion transmembrane transport / voltage-gated potassium channel complex / nervous system development / chemical synaptic transmission ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / Interaction between L1 and Ankyrins / ankyrin binding / voltage-gated potassium channel activity / potassium ion transmembrane transport / voltage-gated potassium channel complex / nervous system development / chemical synaptic transmission / calmodulin binding / synapse / plasma membrane 類似検索 - 分子機能
Potassium channel, voltage dependent, KCNQ2 / Ankyrin-G binding site / Ankyrin-G binding motif of KCNQ2-3 / Unstructured region on Potassium channel subunit alpha KvLQT2 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Ion transport domain / Ion transport protein 類似検索 - ドメイン・相同性
Potassium voltage-gated channel subfamily KQT member 2 類似検索 - 構成要素
National Natural Science Foundation of China (NSFC)
31870724
中国
引用
ジャーナル: Cell Res / 年: 2021 タイトル: Molecular basis for ligand activation of the human KCNQ2 channel. 著者: Xiaoxiao Li / Qiansen Zhang / Peipei Guo / Jie Fu / Lianghe Mei / Dashuai Lv / Jiangqin Wang / Dongwu Lai / Sheng Ye / Huaiyu Yang / Jiangtao Guo / 要旨: 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- ...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.