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|1yc1, resolution 1.70Å ()|
|Gene:||HSPCA, HSP90A, HSPC1 (Homo sapiens)|
Crystal Structures of human HSP90alpha complexed with dihydroxyphenylpyrazoles
A series of dihydroxyphenylpyrazole compounds were identified as a unique class of reversible Hsp90 inhibitors. The crystal structures for two of the identified compounds complexed with the N-terminal ATP binding domain of human Hsp90alpha were determined. The dihydroxyphenyl ring of the compounds fits deeply into the adenine binding pocket with the C2 hydroxyl group forming a direct hydrogen bond with the side chain of Asp93. The pyrazole ring forms hydrogen bonds to the backbone carbonyl of Gly97, the hydroxyl group of Thr184 and to a water molecule, which is present in all of the published HSP90 structures. One of the identified compounds (G3130) demonstrated cellular activities (in Her-2 degradation and activation of Hsp70 promoter) consistent with the inhibition of cellular Hsp90 functions.
Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles., Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y, Lesley SA, Caldwell J, Gu XJ, Bioorg Med Chem Lett. 2005 Mar 1;15(5):1475-8. PMID:15713410
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Kreusch A, Han S, Brinker A, Zhou V, Choi HS, He Y, Lesley SA, Caldwell J, Gu XJ. Crystal structures of human HSP90alpha-complexed with dihydroxyphenylpyrazoles. Bioorg Med Chem Lett. 2005 Mar 1;15(5):1475-8. PMID:15713410 doi:10.1016/j.bmcl.2004.12.087
- Konstantinou-Kirtay C, Mitchell JB, Lumley JA. Scoring functions and enrichment: a case study on Hsp90. BMC Bioinformatics. 2007 Jan 26;8:27. PMID:17257425 doi:10.1186/1471-2105-8-27