CRYSTAL-STRUCTURE OF AN HSP90-GELDANAMYCIN COMPLEX - TARGETING OF A PROTEIN CHAPERONE BY AN ANTITUMOR AGENT

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 geld anamycin 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 substrate s. The structure of the geldanamycin-binding domain of Hsp90 (residues 9-232) reveals a pronounced pocket, 15 Angstrom deep, that is highly conserved across species. Geldanamycin binds inside this pocket, adopt ing a compact structure similar to that of a polypeptide chain in a tu rn conformation. This, and the pocket's similarity to substrate-bindin g sites, suggest that the pocket binds a portion of the polypeptide su bstrate and participates in the conformational maturation/refolding re action.