7D24
Hsp90 alpha N-terminal domain in complex with a 4B compund
Summary for 7D24
| Entry DOI | 10.2210/pdb7d24/pdb |
| Descriptor | Heat shock protein HSP 90-alpha, 9-[(3-tert-butyl-1,2-oxazol-5-yl)methyl]-6-chloranyl-purin-2-amine (3 entities in total) |
| Functional Keywords | chaperone-inhibitor complex, chaperone/inhibitor |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 24418.04 |
| Authors | Shin, S.C.,Kim, E.E. (deposition date: 2020-09-15, release date: 2021-07-28, Last modification date: 2023-11-29) |
| Primary citation | Shin, S.C.,El-Damasy, A.K.,Lee, J.H.,Seo, S.H.,Kim, J.H.,Seo, Y.H.,Lee, Y.,Yu, J.H.,Bang, E.K.,Kim, E.E.,Keum, G. Structural Basis for Design of New Purine-Based Inhibitors Targeting the Hydrophobic Binding Pocket of Hsp90. Int J Mol Sci, 21:-, 2020 Cited by PubMed Abstract: Inhibition of the molecular chaperone heat shock protein 90 (Hsp90) represents a promising approach for cancer treatment. BIIB021 is a highly potent Hsp90 inhibitor with remarkable anticancer activity; however, its clinical application is limited by lack of potency and response. In this study, we aimed to investigate the impact of replacing the hydrophobic moiety of BIIB021, 4-methoxy-3,5-dimethylpyridine, with various five-membered ring structures on the binding to Hsp90. A focused array of /-substituted purines, featuring aromatic and non-aromatic rings, was designed, considering the size of hydrophobic pocket B in Hsp90 to obtain insights into their binding modes within the ATP binding site of Hsp90 in terms of π-π stacking interactions in pocket B as well as outer α-helix 4 configurations. The target molecules were synthesized and evaluated for their Hsp90α inhibitory activity in cell-free assays. Among the tested compounds, the isoxazole derivatives and , and the sole six-membered derivative showed favorable Hsp90α inhibitory activity, with IC values of 1.76 µM, 0.203 µM, and 1.00 µM, respectively. Furthermore, compound 14 elicited promising anticancer activity against MCF-7, SK-BR-3, and HCT116 cell lines. The X-ray structures of compounds , , , , and bound to the -terminal domain of Hsp90 were determined in order to understand the obtained results and to acquire additional structural insights, which might enable further optimization of BIIB021. PubMed: 33317068DOI: 10.3390/ijms21249377 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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