Effects of Inhibitors on Hsp90′s Conformational Dynamics, Cochaperone and Client Interactions

Sonja Schmid*, Markus Götz, Thorsten Hugel

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)


The molecular chaperone and heat-shock protein Hsp90 has become a central target in anti-cancer therapy. Nevertheless, the effect of Hsp90 inhibition is still not understood at the molecular level, preventing a truly rational drug design. Here we report on the effect of the most prominent drug candidates, namely, radicicol, geldanamycin, derivatives of purine, and novobiocin, on Hsp90′s characteristic conformational dynamics and the binding of three interaction partners. Unexpectedly, the global opening and closing transitions are hardly affected by Hsp90 inhibitors. Moreover, we find no significant changes in the binding of the cochaperones Aha1 and p23 nor of the model substrate Δ131Δ. This holds true for competitive and allosteric inhibitors. Therefore, direct inhibition mechanisms affecting only one molecular interaction are unlikely. We suggest that the inhibitory action observed in vivo is caused by a combination of subtle effects, which can be used in the search for novel Hsp90 inhibition mechanisms.

Original languageEnglish
Pages (from-to)1716-1721
Number of pages6
Issue number14
Publication statusPublished - 17 Jul 2018
Externally publishedYes


  • chaperone Hsp90
  • FRET
  • inhibitor
  • protein conformational dynamics
  • single molecule


Dive into the research topics of 'Effects of Inhibitors on Hsp90′s Conformational Dynamics, Cochaperone and Client Interactions'. Together they form a unique fingerprint.

Cite this