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 Hsp90N–RJ19 was determined by X-ray diffraction (resolution limit, 2.0 Å, PDB code 4L90). The crystal structure of Hsp90N–RJ19 was analyzed in detail and compared with that of native Hsp90N, Hsp90N-ATP, and Hsp90N-GDM, respectively. It was indicated that RJ19 interacted with Hsp90N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90N 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 Hsp90N–RJ19 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 Hsp90N provide a rational basis for the design and optimization of novel anticancer drugs.
Heat shock protein 90 Drug target Inhibitor X-ray diffraction Complex crystal structure
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