Raman Swetha, Singh Meetali, Tatu Utpal, Suguna Kaza
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Department of Biochemistry, Indian Institute of Science, Bangalore, India.
Sci Rep. 2015 Nov 24;5:17015. doi: 10.1038/srep17015.
The involvement of Hsp90 in progression of diseases like cancer, neurological disorders and several pathogen related conditions is well established. Hsp90, therefore, has emerged as an attractive drug target for many of these diseases. Several small molecule inhibitors of Hsp90, such as geldanamycin derivatives, that display antitumor activity, have been developed and are under clinical trials. However, none of these tested inhibitors or drugs are peptide-based compounds. Here we report the first crystal structure of a peptide bound at the ATP binding site of the N-terminal domain of Hsp90. The peptide makes several specific interactions with the binding site residues, which are comparable to those made by the nucleotide and geldanamycin. A modified peptide was designed based on these interactions. Inhibition of ATPase activity of Hsp90 was observed in the presence of the modified peptide. This study provides an alternative approach and a lead peptide molecule for the rational design of effective inhibitors of Hsp90 function.
热休克蛋白90（Hsp90）参与癌症、神经紊乱和几种病原体相关疾病等病症的进展已得到充分证实。因此，Hsp90已成为这些疾病中颇具吸引力的药物靶点。已经开发出几种显示出抗肿瘤活性的Hsp90小分子抑制剂，如格尔德霉素衍生物，并且正在进行临床试验。然而，这些经过测试的抑制剂或药物都不是基于肽的化合物。在此，我们报道了一种结合在Hsp90 N端结构域ATP结合位点的肽的首个晶体结构。该肽与结合位点残基形成了几种特定的相互作用，这些相互作用与核苷酸和格尔德霉素形成的相互作用相当。基于这些相互作用设计了一种修饰肽。在修饰肽存在的情况下，观察到Hsp90的ATP酶活性受到抑制。这项研究为合理设计有效的Hsp90功能抑制剂提供了一种替代方法和一个先导肽分子。
