Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent.
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Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP
Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent.
Cell. 1997 Apr 18;89(2):239-50.
- PubMed ID
- 9108479 [ View in PubMed]
- Abstract
The Hsp90 chaperone is required for the activation of several families of eukaryotic protein kinases and nuclear hormone receptors, many of which are protooncogenic and play a prominent role in cancer. The geldanamycin antibiotic has antiproliferative and antitumor effects, as it binds to Hsp90, inhibits the Hsp90-mediated conformational maturation/refolding reaction, and results in the degradation of Hsp90 substrates. The structure of the geldanamycin-binding domain of Hsp90 (residues 9-232) reveals a pronounced pocket, 15 A deep, that is highly conserved across species. Geldanamycin binds inside this pocket, adopting a compact structure similar to that of a polypeptide chain in a turn conformation. This, and the pocket's similarity to substrate-binding sites, suggest that the pocket binds a portion of the polypeptide substrate and participates in the conformational maturation/refolding reaction.