Elucidation of the Hsp90 C-Terminal Inhibitor Binding Site

• Published in: ACS chemical biology 2011-08, Vol.6 (8), p.800-807
• Main Authors: Matts, Robert L, Dixit, Anshuman, Peterson, Laura B, Sun, Liang, Voruganti, Sudhakar, Kalyanaraman, Palgunan, Hartson, Steve D, Verkhivker, Gennady M, Blagg, Brian S. J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Binding Sites; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - chemistry; HSP90 Heat-Shock Proteins - metabolism; Humans; Models, Molecular; Molecular Sequence Data; Novobiocin - chemistry; Novobiocin - pharmacology; Peptide Hydrolases - metabolism; Protein Binding; Protein Structure, Tertiary; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Tandem Mass Spectrometry
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb200052x

The Hsp90 chaperone machine is required for the folding, activation, and/or stabilization of more than 50 proteins directly related to malignant progression. Hsp90 contains small molecule binding sites at both its N- and C-terminal domains; however, limited structural and biochemical data regarding the C-terminal binding site is available. In this report, the small molecule binding site in the Hsp90 C-terminal domain was revealed by protease fingerprinting and photoaffinity labeling utilizing LC–MS/MS. The identified site was characterized by generation of a homology model for hHsp90α using the SAXS open structure of HtpG and docking the bioactive conformation of NB into the generated model. The resulting model for the bioactive conformation of NB bound to Hsp90α is presented herein.