Effects of Inhibitors on Hsp90′s Conformational Dynamics, Cochaperone and Client Interactions. Issue 14 (25th May 2018)

• Record Type: Journal Article
• Authors: Schmid, Sonja; Götz, Markus; Hugel, Thorsten
• Is Part Of: Chemphyschem. Volume 19:Issue 14(2018)
• Page Start: 1716
• Page End: 1721
• Publication Date: 2018-05-25
• Subjects: chaperone Hsp90 -- FRET -- inhibitor -- protein conformational dynamics -- single molecule; Chemistry, Physical and theoretical -- Periodicals; 541.05
• DOI: 10.1002/cphc.201800342
• Languages: English
• ISSNs: 1439-4235

Abstract

Abstract: 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. Abstract : Hypothesis dismissed : The effect of anti‐cancer drug candidates on the central chaperone protein Hsp90 is studied by ensemble and single‐molecule fluorescence experiments (see Figure). Unexpectedly, the most prominent inhibitors have little to no impact on the characteristic conformational dynamics of Hsp90, nor the binding of cochaperones or a client protein.