Tie1调控内皮细胞Ang/Tie通路的结构基础及靶向Tie1的多肽设计

项目名称： Tie1调控内皮细胞Ang/Tie通路的结构基础及靶向Tie1的多肽设计

项目编号： No.31500591

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 刘广建

作者单位： 广州医科大学

项目金额： 20万元

中文摘要： Ang/Tie信号系统是发现于内皮细胞的特异性受体酪氨酸激酶系统，参与肿瘤血管生成的全过程，成为抗肿瘤药物设计的热门靶标。当前研究发现Tie1在Ang/Tie2信号通路中起到分子开关的作用，但具体结构基础并不明晰。本项目拟基于“Tie1与Tie2/Ang-1和Tie2/Ang-2所形成复合物的结构稳定性不同”这一猜想，以构建Tie1-Tie2-Ang(s)结构模型库为切入点，结合同源模建、分子对接、分子动力学、虚拟突变和自由能计算等分子模拟技术，揭示Tie1如何调控Ang-1和Ang-2对Tie2的不同激活效应，阐明这种机制的分子结构基础和关键残基，为进一步澄清Ang/Tie系统的生物学功能以及抗肿瘤药物的设计提供有益借鉴。本项目还拟在系统获取Ang/Tie分子结构信息的基础上，设计靶向Tie1的多肽分子并加以验证，为基于Tie1-Tie2相互作用的靶向小分子多肽先导药物的发现提供新思路。

中文关键词： 蛋白质；动力学；分子模拟；结构稳定性；生物信息学分析

英文摘要： The Ang/Tie signal system is an endothelial cell-specific receptor tyrosine kinase system, which is involved in the whole process of tumor angiogenesis. Therefore, the Ang/Tie system has become a topical target for anti-tumor drugs development. It is reported that Tie1 serves as a “molecular switch” in the Ang/Tie2 pathway, while the underlying structural basis is still not clear. Here, we plan to deploy a fold of studies around the hypothesis that the structural stabilities are different between Tie1/Tie2/Ang-1 and Tie1/Tie2/Ang-2. The project will begin with establishing a structural database of Tie1, Tie2 and Ang(s). Then we will use a set of molecular simulation tools including homology modeling, molecular docking, molecular dynamics simulation, virtual mutation, as well as free energy calculation, to disclose how Tie1 regulates the responses of Tie2 to Ang-1 and Ang-2, to clarify the detailed conformational changes and key residues, and to provide lessons in understanding the biological function of the Ang/Tie system and designing potential anti-tumor drugs. On the basis of above bioinformatics investigations, we will further combine in silico and in vitro approaches to design potent peptides for competitively blocking the recognition and association of Tie1 with Tie2.

英文关键词： Proteins;Dynamics;Molecular Simulation;Structural Stability;Bioinformatics Analysis