An allosteric ligand-binding site in the extracellular cap of K2P channels
文献类型：期刊论文
| 作者 | Luo, Qichao2,3,4; Chen, Liping2,3,4; Cheng, Xi2,3,4; Ma, Yuqin2,3,4; Li, Xiaona2,3,4; Zhang, Bing2,3,4; Li, Li2,3,4; Zhang, Shilei1,5; Guo, Fei2,3,4; Li, Yang2,3,4
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| 刊名 | NATURE COMMUNICATIONS
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| 出版日期 | 2017-08-29 |
| 卷号 | 8 |
| ISSN号 | 2041-1723 |
| DOI | 10.1038/s41467-017-00499-3 |
| 文献子类 | Article |
| 英文摘要 | Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are thus potential drug targets for treating diseases. Here, we identify N-(4-cholorphenyl)-N-(2-(3,4-dihydrosioquinolin-2 (1H)-yl)-2-oxoethyl) methanesulfonamide (TKDC) as an inhibitor of the TREK subfamily, including TREK-1, TREK-2 and TRAAK channels. Using TKDC as a chemical probe, a study combining computations, mutagenesis and electrophysiology reveals a K2P allosteric ligand-binding site located in the extracellular cap of the channels. Molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway. Using virtual screening approach, we identify other inhibitors targeting the extracellular allosteric ligand-binding site of these channels. Overall, our results suggest that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins. |
| WOS关键词 | DOMAIN POTASSIUM CHANNEL ; TRAAK K+ CHANNEL ; MOLECULAR-DYNAMICS ; CRYSTAL-STRUCTURE ; DISULFIDE BRIDGE ; RUTHENIUM RED ; TREK-1 ; SUBUNITS ; TWIK-1 ; SENSITIVITY |
| 资助项目 | National Natural Science Foundation of China[21422208] ; Ministry of Science and Technology of the People's Republic of China[2013CB910601] ; Ministry of Science and Technology of the People's Republic of China[2013CB910604] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040302] ; National Key Scientific Instrument & Equipment Development Program of China[2012YQ0306010] ; E-Institutes of Shanghai Municipal Education Commission[E09013] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE PUBLISHING GROUP |
| WOS记录号 | WOS:000408547200009 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272520]  |
| 专题 | 药理学第二研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Li, Yang; Yang, Huaiyu |
| 作者单位 | 1.Soochow Univ, Coll Pharmaceut Sci, Dept Med Chem, 199 Renai Rd, Suzhou 215123, Peoples R China; 2.Chinese Acad Sci, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 5.Soochow Univ, Jiangsu Key Lab Translat Res & Therapy Neuropsych, 199 Renai Rd, Suzhou 215123, Peoples R China; 6.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, 500 Dongchuan Rd, Shanghai 200241, Peoples R China; 7.East China Normal Univ, Sch Life Sci, 500 Dongchuan Rd, Shanghai 200241, Peoples R China |
| 推荐引用方式 GB/T 7714 | Luo, Qichao,Chen, Liping,Cheng, Xi,et al. An allosteric ligand-binding site in the extracellular cap of K2P channels[J]. NATURE COMMUNICATIONS,2017,8. |
| APA | Luo, Qichao.,Chen, Liping.,Cheng, Xi.,Ma, Yuqin.,Li, Xiaona.,...&Yang, Huaiyu.(2017).An allosteric ligand-binding site in the extracellular cap of K2P channels.NATURE COMMUNICATIONS,8. |
| MLA | Luo, Qichao,et al."An allosteric ligand-binding site in the extracellular cap of K2P channels".NATURE COMMUNICATIONS 8(2017). |
入库方式： OAI收割
来源：上海药物研究所
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