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.
Original language | English |
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Pages (from-to) | 775-785 |
Number of pages | 11 |
Journal | Chemistry & Biology |
Volume | 11 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 2004 |
Keywords
- IN-VIVO FUNCTION
- MOLECULAR CHAPERONE
- ATP-BINDING
- PROTEIN MODELS
- CANCER CELLS
- HEAT-SHOCK-PROTEIN-90
- REFINEMENT
- HYDROLYSIS
- RADICICOL
- TARGET