ATP依赖的Hsp90构像变化和药物发现研究

分子伴侣蛋白（蛋白质折叠）和泛素-蛋白水解酶体系统（蛋白质降解）共同构成了蛋白质的质量控制体系，维持生物体蛋白质的生成和降解平衡。Hsp90是分子伴侣蛋白家族的重要成员，抗肿瘤药物研发的靶点。Hsp90具有ATP水解酶活性，ATP结合和水解所引发的Hsp90的构像变化对于Hsp90整个功能执行过程的完成至关重要，然而截至目前为止，我们对于这一过程的了解尚远未明晰。本课题拟采用NMR技术和计算机分子模拟技术开展自由态Hsp90 N端和中间结构域以及它们与AMP-PNP（ATP类似物）所形成复合物的结构解析和动力学行为研究，研究结果将阐明ATP依赖的Hsp90构像变化的动力学分子机制。此外，我们将根据NMR结构生物学的研究结果寻找Hsp90的变构调节位点，筛选并设计Hsp90中间结构域的变构抑制剂，为抗肿瘤药物研发提供新型的先导化合物。

Protein quality control system is composed of molecular chaperones (for protein folding) and ubiquitin-proteasome pathway (for protein degradation), which play key roles in the maintenance of protein homeostasis in cell. Hsp90 is one of the most important chaperones, and a target for anticancer drug discovery. Hsp90 possesses ATPase activity, and the induced conformational changes of Hsp90 by the binding and hydrolysis of ATP are coupled to its function, however, up to date, this process is far from to be fully understood. We will use NMR and molecular dynamics simulation techniques to solve the solution structures and investigate the dynamic behaviors of the N-terminal and middle domains of Hsp90 in the absence and presence of AMP-PNP (ATP analogue), which will unravel the dynamic molecular mechanism of ATP-dependent conformational changes of Hsp90. Moreover, based on the structural biology research results the allosteric modulator binding sites for the middle domain of Hsp90 will be identified. By virtual screening and drug design the allosteric inhibitors for the middle domain of Hsp90 will be obtained, and some of them will become novel anticancer drug leads.