Conformational dynamics of the molecular chaperone Hsp90 in complexes with a co-chaperone and anticancer drugs.
The molecular chaperone Hsp90 is essential for the correct folding, maturation and activation of a diverse array of client proteins, including several key constituents of oncogenic processes. Hsp90 has become a focus of cancer research, since it represents a target for direct prophylaxis against multistep malignancy. Hydrogen-exchange mass spectrometry was used to study the structural and conformational changes undergone by full-length human Hsp90beta in solution upon binding of the kinase-specific co-chaperone Cdc37 and two Hsp90 ATPase inhibitors: Radicicol and the first-generation anticancer drug DMAG. Changes in hydrogen exchange pattern in the complexes in regions of Hsp90 remote to the ligand-binding site were observed indicating long-range effects. In particular, the interface between the N-terminal domain and middle domains exhibited significant differences between the apo and complexed forms. For the inhibitors, differences in the interface between the middle domain and the C-terminal domain were also observed. These data provide important insight into the structure of the biologically active form of the protein.
Phillips
Jonathan J
JJ
Cambridge University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK; Department of Biochemistry, University of Cambridge, Old Addenbrookes Site, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.
Yao
Zhong-ping
ZP
Zhang
Wei
W
McLaughlin
Stephen
S
Laue
Ernest D
ED
Robinson
Carol V
CV
Jackson
Sophie E
SE
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D018833:Chaperonins / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism; D046911:Macromolecular Substances; D013058:Mass Spectrometry; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary
D000970:Antineoplastic Agents; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D020033:Protein Isoforms; D018833:Chaperonins; C035359:monorden