作用钾通道KCNQ1特异性多肽的分子设计及功能机制研究

项目名称： 作用钾通道KCNQ1特异性多肽的分子设计及功能机制研究

项目编号： No.31200557

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 陈宗运

作者单位： 武汉大学

项目金额： 25万元

中文摘要： KCNQ1钾通道与众多生理病理过程密切相关。因缺乏特异性多肽调节剂，其结构功能研究进展缓慢。项目申请人自2007年开始从事作用钾通道KCNQ1特异性多肽的筛选设计研究，大量实验发现了KCNQ1钾通道对经典碱性蝎毒素多肽不敏感，对系列新型酸性蝎毒素多肽弱敏感（Kd值约为11μM，相关结果发表在PLoS ONE,2012），对近中性多肽较敏感（Kd值约为1-4.6μM）。据此，本项目拟以近中性多肽为模板，运用蝎毒素多肽-钾通道相互作用的生物学信息和计算机辅助设计的策略，合理设计系列潜在作用钾通道KCNQ1的多肽调节剂，通过电生理实验鉴定特异性多肽。在此基础上，深入研究钾通道KCNQ1与特异性多肽相互作用的分子机制，阐明其对不同的毒素多肽敏感和耐受的结构基础，为以特异性多肽作为新型"分子探针"研究KCNQ1钾通道结构功能及生理病理过程中的作用奠定理论基础，提供科学依据。

中文关键词： KCNQ1；多肽；分子设计；Ascaris结构模体；

英文摘要： KCNQ1 channel has been proved to associate with many physiological and pathological processes. However, the structural and functional research of KCNQ1 channel progressed slowly for the lacking of potent peptide inhibitors as probes. Project applicant has started to screen KCNQ1 channel-speicific peptides from scorpion venom since 2007. Many experimental data have showed that KCNQ1 channel was not sensitive to classcial basic scorpion toxins, but novel acidic scorpion toxins have weak activities towards KCNQ1 channel (with Kd of about 11μM, PLoS ONE,2012), and near-neutral scorpion toxins have better acitivities(with Kd of about 1-4.6μM). On the base of these studies, we will chose near-neutral scorpion toxins as template in this project, and focus our attentions on the molecular design with the help of molecular dymamics simuation and laws of toxin-potassium channel interaction. Electrophysiological experiments will be used to test the activities of a series of designed pepitdes. Finally, potent inhibitors spicific for KCNQ1channel will be selected. Using potent pepitdes as probes, we will further research the structure-function relationship of KCNQ1 channel interacting with peptide inhibitors and explain the molecualr mechinism of peptide recognizing KCNQ1 channel. Our research will lay the theoretical found

英文关键词： KCNQ1；Peptide；Molecular design；Ascaris sructural fold；