Elucidation of the Hsp90 C-terminal inhibitor binding site

ACS Chem Biol. 2011 Aug 19;6(8):800-7. doi: 10.1021/cb200052x. Epub 2011 May 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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


  • Anti-Bacterial Agents
  • HSP90 Heat-Shock Proteins
  • Small Molecule Libraries
  • Novobiocin
  • Peptide Hydrolases