Complex structure of human Hsp90N and a novel small inhibitor FS5
Complex structure of human Hsp90N and a novel small inhibitor FS5
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DOI：
10.1007/s41365-020-0739-3
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发表时间：
2020-02
影响因子：
2.8
通讯作者：
Ruihuan Liu;Xiaoxing Lu;Xiangdong Huang;Wei-Dong He;J. Duan;Jin Zhang;Jian Li
中科院分区：
文献类型：
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作者：
Ruihuan Liu;Xiaoxing Lu;Xiangdong Huang;Wei-Dong He;J. Duan;Jin Zhang;Jian Li
热休克蛋白 (Hsps) 是一个大量表达的 ATP 依赖性伴侣蛋白家族。 Hsp90 是 Hsp 家族的杰出成员。迄今为止，Hsp90的两个主要功能已被描述：首先，作为一些蛋白激酶和核激素受体构象变化的调节剂，另一个是细胞应激反应中不可或缺的因子。 Hsp90具有数量必需的相互作用蛋白，因为它参与几乎所有的生物过程，其重要性不言而喻。 Hsp90与癌症的发病机制，特别是癌细胞的增殖和照射有着密不可分的关系，因此是一个值得注意的癌症靶点。自从从吸水链霉菌中发现第一个 Hsp90 抑制剂格尔德霉素以来，更多的注意力集中在 Hsp90 上。许多基于结构的 Hsp90 抑制剂已被设计用于开发一种战胜癌症的创新方法。然而，已经设计的抑制剂存在各种缺陷，如肝毒性、水溶性差、不稳定、口服生物利用度不理想等。基于上述原因，为了达到最佳的性能和更少的副作用，我们设计了一种新型的Hsp90抑制剂，称为FS5，并解析了Hsp90N-FS5复合物的晶体结构（1.65 Å，PDB代码5XRB）。此外，我们比较了Hsp90N、Hsp90N-GDM和Hsp90N-ATP复合物，表明抑制剂FS5可能与ATP竞争结合Hsp90，这可以被视为未来开发新型抗癌药物的潜在策略。
Heat shock proteins (Hsps) are a family of abundantly expressed ATP-dependent chaperone proteins. Hsp90 is an eminent member of Hsp family. Thus far, two primary functions have been described for Hsp90: first, as a regulator of conformational change of some protein kinases and nuclear hormone receptors, and the other as an indispensable factor in cellular stress response. Hsp90 has an essential number of interaction proteins since it participates in almost every biological process and its importance is self-evident. Hsp90 has an inextricable relationship in the pathogenesis of cancer, especially in the proliferation and irradiation of cancer cells, thus being a notable cancer target. Since the discovery of geldanamycin, the first inhibitor of Hsp90, from the bacterial speciesStreptomyces hygroscopicus, even more attention has been focused toward Hsp90. Many structure-based inhibitors of Hsp90 have been designed to develop an innovative method to defeat cancer. However, already designed inhibitors have various deficiencies, such as hepatotoxicity, poor aqueous solubility, instability, and non-ideal oral bioavailability. Based on the aforementioned reasons and to achieve an optimal performance and fewer side effects, we designed a novel inhibitor of Hsp90, called FS5, and resolved the crystal structure of the Hsp90N-FS5 complex (1.65 Å, PDB code 5XRB). Furthermore, we compared the complexes Hsp90N, Hsp90N-GDM, and Hsp90N-ATP and suggest that the inhibitor FS5 may compete with ATP for binding to Hsp90, which can be regarded as a potential strategy for the development of novel cancer drugs in the future.