The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands
文献类型：期刊论文
| 作者 | Li, Ping2; Chen, Zhuxi3; Xu, Haiyan2; Sun, Haifeng3; Li, Hao3; Liu, Hong3 ; Yang, Huaiyu3; Gao, Zhaobing2; Jiang, Hualiang3; Li, Min1,2,4
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| 刊名 | CELL RESEARCH
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| 出版日期 | 2013-09 |
| 卷号 | 23期号:9页码:1106-1118 |
| ISSN号 | 1001-0602 |
| 关键词 | voltage-gated potassium channel gating charge pathway KCNQ2 activator binding site anti-epilepsy drug |
| DOI | 10.1038/cr.2013.82 |
| 文献子类 | Article |
| 英文摘要 | Voltage-gated potassium (Kv) channels derive their voltage sensitivity from movement of gating charges in voltage-sensor domains (VSDs). The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kv1.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and electrophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel activators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel. |
| WOS关键词 | SHAKER K+ CHANNEL ; VOLTAGE-SENSING DOMAIN ; GATED PROTON CHANNEL ; MOLECULAR-DYNAMICS ; TRANSMEMBRANE MOVEMENT ; PERMEATION PATHWAY ; STRUCTURAL BASIS ; RESTING STATE ; SENSOR ; PORE |
| 资助项目 | State Key Development Program for Basic Research of China[2013CB910604] ; State Key Development Program for Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[81072579] ; National Natural Science Foundation of China[81173027] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[81230076] ; Shanghai Science and Technology Development Funds[12QA1404000] ; National Institute of Health[MH084691] ; National Institute of Health[GM070959] |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4919750 |
| 出版者 | INST BIOCHEMISTRY & CELL BIOLOGY |
| WOS记录号 | WOS:000323930200009 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277480]  |
| 专题 | 神经药理学研究国际科学家工作站 中科院受体结构与功能重点实验室 成果转移转化处 新药研究国家重点实验室 药物发现与设计中心 |
| 通讯作者 | Jiang, Hualiang |
| 作者单位 | 1.Johns Hopkins Univ, High Throughput Biol Ctr, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Johns Hopkins Univ, Sch Med, Johns Hopkins Ion Channel Ctr, Baltimore, MD 21205 USA |
| 推荐引用方式 GB/T 7714 | Li, Ping,Chen, Zhuxi,Xu, Haiyan,et al. The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands[J]. CELL RESEARCH,2013,23(9):1106-1118. |
| APA | Li, Ping.,Chen, Zhuxi.,Xu, Haiyan.,Sun, Haifeng.,Li, Hao.,...&Li, Min.(2013).The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands.CELL RESEARCH,23(9),1106-1118. |
| MLA | Li, Ping,et al."The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands".CELL RESEARCH 23.9(2013):1106-1118. |
入库方式： OAI收割
来源：上海药物研究所
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