TY - JOUR
T1 - Effects of Inhibitors on Hsp90′s Conformational Dynamics, Cochaperone and Client Interactions
AU - Schmid, Sonja
AU - Götz, Markus
AU - Hugel, Thorsten
PY - 2018/7/17
Y1 - 2018/7/17
N2 - 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.
AB - 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.
KW - chaperone Hsp90
KW - FRET
KW - inhibitor
KW - protein conformational dynamics
KW - single molecule
UR - http://www.scopus.com/inward/record.url?scp=85050180827&partnerID=8YFLogxK
U2 - 10.1002/cphc.201800342
DO - 10.1002/cphc.201800342
M3 - Article
AN - SCOPUS:85050180827
SN - 1439-4235
VL - 19
SP - 1716
EP - 1721
JO - ChemPhysChem
JF - ChemPhysChem
IS - 14
ER -