Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone.
Hsp90 molecular chaperones in eukaryotic cells play essential roles in the folding and activation of a range of client proteins involved in cell cycle regulation, steroid hormone responsiveness, and signal transduction. The biochemical mechanism of Hsp90 is poorly understood, and the involvement of ATP in particular is controversial. Crystal structures of complexes between the N-terminal domain of the yeast Hsp90 chaperone and ADP/ATP unambiguously identify a specific adenine nucleotide binding site homologous to the ATP-binding site of DNA gyrase B. This site is the same as that identified for the antitumor agent geldanamycin, suggesting that geldanamycin acts by blocking the binding of nucleotides to Hsp90 and not the binding of incompletely folded client polypeptides as previously suggested. These results finally resolve the question of the direct involvement of ATP in Hsp90 function.
Prodromou
C
C
Department of Biochemistry and Molecular Biology, University College London, United Kingdom.
Roe
S M
SM
O'Brien
R
R
Ladbury
J E
JE
Piper
P W
PW
Pearl
L H
LH
D000244:Adenosine Diphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016227:Benzoquinones; D001665:Binding Sites; D002151:Calorimetry; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D008958:Models, Molecular; D008961:Models, Structural; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011809:Quinones / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D016415:Sequence Alignment
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D000244:Adenosine Diphosphate; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II; C001277:geldanamycin