6lt8
HSP90 in complex with KW-2478
Structural highlights
FunctionHS90A_HUMAN Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedKW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 (N) (Hsp90(N)). Absence of complex crystal structure of Hsp90(N)-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90(N)-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 A; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, DeltaTm, 18.82 +/- 0.51 degrees C) and isothermal titration calorimetry (ITC, Kd, 7.30 +/- 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90(N). Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16 muM for A549; 14.29 muM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90(N)-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90(N) evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478. Anti-NSCLC activity in vitro of Hsp90(N) inhibitor KW-2478 and complex crystal structure determination of Hsp90(N)-KW-2478.,Li HJ, Wang QS, Han W, Zhou H, Li P, Zhou F, Qin W, Zhao D, Zhou X, He CX, Xing L, Li PQ, Jin X, Yu F, He JH, Cao HL J Struct Biol. 2021 Jun;213(2):107710. doi: 10.1016/j.jsb.2021.107710. Epub 2021 , Feb 19. PMID:33610655[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
