Nuclear Science and Techniques

《核技术》(英文版) ISSN 1001-8042 CN 31-1559/TL     2019 Impact factor 1.556

Nuclear Science and Techniques ›› 2020, Vol. 31 ›› Issue (3): 30 doi: 10.1007/s41365-020-0739-3

• NUCLEAR PHYSICS AND INTERDISCIPLINARY RESEARCH • Previous Articles     Next Articles

Complex structure of human Hsp90N and a novel small inhibitor FS5

Rui Liu1,2 • Xiao-Lu Lu2 • Xian-Hua Huang2 • Wei He2 • Jing-Jing Duan3 • Jin Zhang1 • Jian Li2,4   

  1. 1 School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China
    2 College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China
    3 Human Aging Research Institute (HARI), School of Life Sciences, Nanchang University, Nanchang 330031, China
    4 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China
  • Received:2019-12-15 Revised:2020-01-15 Accepted:2020-01-18
  • Contact: Jian Li E-mail:rmsl_2040@163.com
  • Supported by:
    This work was supported by the Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education (No. XN201904), Gannan Medical University (No. QD201910), the National Natural Science Foundation of China (Nos. 31770795 and 31971043), and the Jiangxi Province Natural Science Foundation (No. 20181ACB20014).
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Rui Liu, Xiao-Lu Lu, Xian-Hua Huang, Wei He, Jing-Jing Duan, Jin Zhang, Jian Li. Complex structure of human Hsp90N and a novel small inhibitor FS5.Nuclear Science and Techniques, 2020, 31(3): 30     doi: 10.1007/s41365-020-0739-3

Abstract: 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 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.

Key words: Heat shock protein 90, Complex crystal structure, Interactions, Anti-tumor drugs, X-ray diffraction