Complex structure of human Hsp90 N and a novel small inhibitor FS5

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 species Streptomyces 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 Hsp90 N -FS5 complex (1.65 Å, PDB code 5XRB). Furthermore, we compared the complexes Hsp90 N , Hsp90 N -GDM, and Hsp90 N -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.