General Pharmacological Activation Mechanism of K+ Channels Bypassing Channel Gates
文献类型：期刊论文
| 作者 | Liu, Shijie3; Guo, Peipei3; Wang, Kun3; Zhang, Shaoying3; Li, Ya3; Shen, Juwen3; Mei, Lianghe2; Ye, Yangliang1; Zhang, Qiansen3; Yang, Huaiyu3 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-07-25 |
| 页码 | 15 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.1c02115 |
| 通讯作者 | Yang, Huaiyu(hyyang@bio.ecnu.edu.cn) |
| 英文摘要 | Under the known pharmacological activation mecha-nisms, activators allosterically or directly open potassium channel gates. However, herein, molecular dynamics simulations on TREK-1, a member of the channel class gated at the filter, suggested that negatively charged activators act with a gate-independent mechanism where compounds increase currents by promoting ions passing through the central cavity. Then, based on studies of KCNQ2, we uncovered that this noncanonical activation mechanism is shared by the other channel class gated at the helix-bundle crossing. Rational drug design found a novel KCNQ2 agonist, CLE030, which stably binds to the central cavity. Functional analysis, molecular dynamics simulations, and calculations of the potential of mean force revealed that the carbonyl oxygen of CLE030 influences permeant ions in the central cavity to contribute to its activation effects. Together, this study discovered a ligand-to-ion activation mechanism for channels that bypasses their gates and thus is conserved across subfamilies with different gates. |
| WOS关键词 | POTASSIUM CHANNELS ; KV7 CHANNELS ; SELECTIVITY ; BINDING ; POTENT ; K-2P ; SENSITIVITY ; MODULATION ; RETIGABINE ; DOCKING |
| 资助项目 | Ministry of Science and Technology[2018YFA0508100] ; National Natural Science Foundation of China[31800699] ; Fundamental Research Funds for the Central Universities ; ECNU[44300-19311-542500/006] ; innovative research team of high-level local universities in Shanghai[SHSMU-ZDCX20211201] ; ECNU Multifunctional Platform for Innovation[001] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000833918800001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302019]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Yang, Huaiyu |
| 作者单位 | 1.Suzhou AlphaMa Biotechnol Co Ltd, Suzhou 215123, Peoples R China 2.Chinese Acad Sci, Suzhou Inst Drug Innovat, Shanghai Inst Mat Med, Suzhou 215123, Jiangsu, Peoples R China 3.East China Normal Univ, Sch Life Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Shijie,Guo, Peipei,Wang, Kun,et al. General Pharmacological Activation Mechanism of K+ Channels Bypassing Channel Gates[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:15. |
| APA | Liu, Shijie.,Guo, Peipei.,Wang, Kun.,Zhang, Shaoying.,Li, Ya.,...&Yang, Huaiyu.(2022).General Pharmacological Activation Mechanism of K+ Channels Bypassing Channel Gates.JOURNAL OF MEDICINAL CHEMISTRY,15. |
| MLA | Liu, Shijie,et al."General Pharmacological Activation Mechanism of K+ Channels Bypassing Channel Gates".JOURNAL OF MEDICINAL CHEMISTRY (2022):15. |
入库方式： OAI收割
来源：上海药物研究所
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