单一靶点抑制剂的临床耐药频繁发生使人们重新重视可同时影响多种与肿瘤相关蛋白的Hsp90，但对该分子的理解还很不够。毛壳素具有体内外抗肿瘤作用，可以抑制G9a, SUV39H1 and TrxR1等蛋白活性，但一直作为SUV39H1抑制剂而应用。我们的前期工作表明（Oncotarget. 2015;6(7):5263-74），毛壳素更应是一种作用新位点的Hsp90抑制剂。本项目拟进一步明确毛壳素结合于Hsp90的C端以及作用的特点，并详细解析其结合于Hsp90的作用位点，为设计同类化合物靶向Hsp90的抑制剂提供分子模板。进而研究毛壳素对Hsp90功能影响的分子机制，在此基础上以已明确Hsp90作用位点的抑制剂毛壳素、17-AAG、Novobiocin、顺铂为探针，寻找Hsp90对客户蛋白识别与其结构关系的规律，为揭示Hsp90的结构与功能以及今后寻找针对Hsp90特异性抑制剂提供理论依据。

Recently, Hsp90 was paid more attention again because the increasing resistances of single target inhibitors in clinical practice, but we don't know a lot about it yet. As an anticancer agent, Chaetocin inhibits the activities of G9a, SUV39H1 and TrxR1, but has recognized as an inhibitor of SUV39H1 for long time. On basis of our primarily studied （Oncotarget. 2015;6(7):5263-74.）, Chaetocin should be considered as a Hsp90 inhibitor with a new binding site. In the study, we intend to assure that Chaetocin interacts with the C-terminal of Hsp90, and analyze the action site on Hsp90 binding to Chaetocin. Next, the mechanisms underlying the functions of Hsp90 will be studied by Chaetocin to provide new molecule template for devising new compounds. Furthermore, we plan to use several known inhibitors of Hsp90 to investigate the law of Hsp90 selecting client protein, laying the foundation to declose the structure and fuction of Hsp90 and providing the supports for discovering new specific inhibitor of Hsp90.