Conformational dynamics of the molecular chaperone Hsp90 in complexes with a co-chaperone and anticancer drugs.

Journal article

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.

Authors: Phillips, J; Yao, Z; Zhang, W; McLaughlin, S; Laue, E

• Publication status: Published
• Journal: Journal of molecular biology
• Volume: 372
• Issue: 5
• Pages: 1189-1203
• Publication date: 2007-10-01
• DOI: 10.1016/j.jmb.2007.04.059
• EISSN: 1089-8638
• ISSN: 0022-2836
• Language: English
• Keywords: Molecular Chaperones; Macrolides; Protein Structure, Tertiary; Antineoplastic Agents; Mass Spectrometry; HSP90 Heat-Shock Proteins; Cell Cycle Proteins; Chaperonins; Enzyme Inhibitors; Protein Isoforms; Amino Acid Sequence; Molecular Sequence Data; Models, Molecular; Binding Sites; Humans; Macromolecular Substances