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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.

Original publication




Journal article


J Mol Biol

Publication Date





1189 - 1203


Amino Acid Sequence, Antineoplastic Agents, Binding Sites, Cell Cycle Proteins, Chaperonins, Enzyme Inhibitors, HSP90 Heat-Shock Proteins, Humans, Macrolides, Macromolecular Substances, Mass Spectrometry, Models, Molecular, Molecular Chaperones, Molecular Sequence Data, Protein Isoforms, Protein Structure, Tertiary