6LT8

HSP90 in complex with KW-2478

Summary for 6LT8

• Entry DOI: 10.2210/pdb6lt8/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 2-[2-ethyl-6-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]carbonyl-3,5-bis(oxidanyl)phenyl]-~{N},~{N}-bis(2-methoxyethyl)ethanamide (3 entities in total)
• Functional Keywords: hsp90, kw-2478, chaperone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 28975.36

Authors

Cao, H.L. (deposition date: 2020-01-21, release date: 2021-01-27, Last modification date: 2023-11-29)

Primary citation

Li, H.J.,Wang, Q.S.,Han, W.,Zhou, H.,Li, P.,Zhou, F.,Qin, W.,Zhao, D.,Zhou, X.,He, C.X.,Xing, L.,Li, P.Q.,Jin, X.,Yu, F.,He, J.H.,Cao, H.L.
Anti-NSCLC activity in vitro of Hsp90 N inhibitor KW-2478 and complex crystal structure determination of Hsp90 N -KW-2478.
J.Struct.Biol., 213:107710-107710, 2021

PubMed Abstract: KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90  (Hsp90). Absence of complex crystal structure of Hsp90-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-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; 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, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, K, 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. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC, 8.16 μM for A549; 14.29 μM 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-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90 evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.

PubMed: 33610655
DOI: 10.1016/j.jsb.2021.107710

Experimental method

X-RAY DIFFRACTION (1.593 Å)