title: The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation.
abstract: Many functions of the chaperone, heat shock protein 90 (hsp90), are inhibited by the drug geldanamycin that specifically binds hsp90. We have studied an amino-terminal domain of hsp90 whose crystal structure has recently been solved and determined to contain a geldanamycin-binding site. We demonstrate that, in solution, drug binding is exclusive to this domain. This domain also binds ATP linked to Sepharose through the gamma-phosphate. Binding is specific for ATP and ADP and is inhibited by geldanamycin. Mutation of four glycine residues within two proposed ATP binding motifs diminishes both geldanamycin binding and the ATP-dependent conversion of hsp90 to a conformation capable of binding the co-chaperone p23. Since p23 binding requires regions outside the 1-221 domain of hsp90, these results indicate a common site for nucleotides and geldanamycin that regulates the conformation of other hsp90 domains.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Graduate School, Rochester, Minnesota 55905, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Grenert
authors.forename: W P
authors.initials: WP
authors.lastname: Sullivan
authors.forename: P
authors.initials: P
authors.lastname: Fadden
authors.forename: T A
authors.initials: TA
authors.lastname: Haystead
authors.forename: J
authors.initials: J
authors.lastname: Clark
authors.forename: E
authors.initials: E
authors.lastname: Mimnaugh
authors.forename: H
authors.initials: H
authors.lastname: Krutzsch
authors.forename: H J
authors.initials: HJ
authors.lastname: Ochel
authors.forename: T W
authors.initials: TW
authors.lastname: Schulte
authors.forename: E
authors.initials: E
authors.lastname: Sausville
authors.forename: L M
authors.initials: LM
authors.lastname: Neckers
authors.forename: D O
authors.initials: DO
authors.lastname: Toft
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011485:Protein Binding; D011487:Protein Conformation; D011809:Quinones / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C001277:geldanamycin