Volume 31, No 1, Jan 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 1, January 2021: 52-61

ORIGINAL ARTICLES

Molecular basis for ligand activation of the human KCNQ2 channel

Xiaoxiao Li¹ , Qiansen Zhang² , Peipei Guo² , Jie Fu² , Lianghe Mei³ , Dashuai Lv⁴ , Jiangqin Wang¹ , Dongwu Lai⁵ , Sheng Ye^4,5 , Huaiyu Yang^2,* , Jiangtao Guo^1,5,*

¹Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
²Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China
³Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 108 Yuxin Road, Suzhou, Jiangsu 215123, China
⁴Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China
⁵Department of Cardiology, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China
⁶School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China
These authors contributed equally: Xiaoxiao Li, Qiansen Zhang, Peipei Guo Correspondence: Huaiyu Yang(hyyang@bio.ecnu.edu.cn)Jiangtao Guo(jiangtaoguo@zju.edu.cn)

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.

https://doi.org/10.1038/s41422-020-00410-8

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