1UYI

Human Hsp90-alpha with 8-(2,5-dimethoxy-benzyl)-2-fluoro-9-pent-9H-purin-6-ylamine

Summary for 1UYI

• Entry DOI: 10.2210/pdb1uyi/pdb
• Related: 1BYQ 1OSF 1UY6 1UY7 1UY8 1UY9 1UYC 1UYD 1UYE 1UYF 1UYG 1UYH 1UYK 1UYL 1UYM 1YER 1YES 1YET
• Descriptor: HEAT SHOCK PROTEIN HSP 90-ALPHA, 8-(2,5-DIMETHOXY-BENZYL)-2-FLUORO-9-PENT-9H-PURIN-6-YLAMINE (3 entities in total)
• Functional Keywords: hsp90, atpase, puz, chaperone, atp-binding, heat shock
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : P07900
• Total number of polymer chains: 1
• Total formula weight: 26980.20

Authors

Wright, L.,Barril, X.,Dymock, B.,Sheridan, L.,Surgenor, A.,Beswick, M.,Drysdale, M.,Collier, A.,Massey, A.,Davies, N.,Fink, A.,Fromont, C.,Aherne, W.,Boxall, K.,Sharp, S.,Workman, P.,Hubbard, R.E. (deposition date: 2004-03-02, release date: 2004-07-01, Last modification date: 2023-12-13)

Primary citation

Wright, L.,Barril, X.,Dymock, B.,Sheridan, L.,Surgenor, A.,Beswick, M.,Drysdale, M.,Collier, A.,Massey, A.,Davies, N.,Fink, A.,Fromont, C.,Aherne, W.,Boxall, K.,Sharp, S.,Workman, P.,Hubbard, R.E.
Structure-Activity Relationships in Purine-Based Inhibitor Binding to Hsp90 Isoforms
Chem.Biol., 11:775-, 2004

PubMed Abstract: Inhibition of the ATPase activity of the chaperone protein HSP90 is a potential strategy for treatment of cancers. We have determined structures of the HSP90alpha N-terminal domain complexed with the purine-based inhibitor, PU3, and analogs with enhanced potency both in enzyme and cell-based assays. The compounds induce upregulation of HSP70 and downregulation of the known HSP90 client proteins Raf-1, CDK4, and ErbB2, confirming that the molecules inhibit cell growth by a mechanism dependent on HSP90 inhibition. We have also determined the first structure of the N-terminal domain of HSP90beta, complexed with PU3. The structures allow a detailed rationale to be developed for the observed affinity of the PU3 class of compounds for HSP90 and also provide a structural framework for design of compounds with improved binding affinity and drug-like properties.

PubMed: 15217611
DOI: 10.1016/J.CHEMBIOL.2004.03.033

Experimental method

X-RAY DIFFRACTION (2.2 Å)