Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attent...Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.展开更多
基金supported by the National Natural Science Foundation of China(Nos.31401185 and 81402850)the Introduced talents Foundation of Xi'an Medical University(No.2015 RCYJ 01)
文摘Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.
