超大动态分子伴侣蛋白Hsp90与其底物分子的作用机理研究

对很多蛋白分子而言，分子伴侣蛋白的辅助是确保其在细胞内正确折叠从而正常行使生物功能的关键因子。作为最重要的分子伴侣蛋白之一，热休克蛋白90（Hsp90）广泛参与人体内多达数百种蛋白的折叠、活化或重组，受其调控的蛋白几乎涵盖了所有基本的生物信号通路传导。作为重要的抗癌分子靶点蛋白，分子伴侣Hsp90已成为目前国际上的研究热点之一。然而，Hsp90蛋白与其底物分子的动态结合使得相关复合体的结构信息极为匮乏，这严重阻碍了人们对于其功能机理的认知。本项目拟以生物核磁共振为主要研究方法，并结合其他生物物理以及生物化学手段，对人源Hsp90蛋白的结构、动态特性以及其与底物复合体结构解析做深入系统的研究，力图揭示分子伴侣Hsp90与其底物分子的相互作用机理，并初步阐明其功能机制，为以该蛋白为分子靶点的药物设计提供理论基础和设计思路。

Proper folding and therefore functioning of many nascent polypeptides often requires assistance from a class of proteins called molecular chaperones. An especially important chaperone is the heat shock protein Hsp90, which interacts with a large and diverse group of substrate proteins, promoting their folding and function. It has been established that the large number of Hsp90 client proteins are implicated in most cellular signaling pathways, and Hsp90 is key to the stability and function of a host of proteins that are important to the cancer cell. This makes Hsp90 an attractive anticancer drug target and a hot topic of current research. Mechanistic understanding of the function of this protein, however, has been greatly hampered by the scarcity of structural knowledge that how Hsp90 dynamically recognizes and interacts with its client proteins. By marring modern NMR methods with other biophysical and biochemical techniques, this project will focus primarily on structure determination and dynamics characterization of Hsp90，as well as that of the Hsp90-substrate complex, aiming to gain a mechanistic understanding of how Hsp90 interacts with its client proteins, and ultimately, to provide insights in developing therapeutic strategies against cancers.