title: Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent.
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.
authors.affiliation: Department of Biochemistry and Structural Biology, Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Stebbins
authors.forename: A A
authors.initials: AA
authors.lastname: Russo
authors.forename: C
authors.initials: C
authors.lastname: Schneider
authors.forename: N
authors.initials: N
authors.lastname: Rosen
authors.forename: F U
authors.initials: FU
authors.lastname: Hartl
authors.forename: N P
authors.initials: NP
authors.lastname: Pavletich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism; D016227:Benzoquinones; D002417:Cattle; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011809:Quinones / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; C001277:geldanamycin