Dual inhibition of chaperoning process by taxifolin: Molecular dynamics simulation study

Hsp90 (heat shock protein 90), a molecular chaperone, stabilizes more than 200 mutated and over expressed oncogenic proteins in cancer development. Cdc37 (cell division cycle protein 37), a co-chaperone of Hsp90, has been found to facilitate the maturation of protein kinases by acting as an adaptor and load these kinases onto the Hsp90 complex. Taxifolin (a natural phytochemical) was found to bind at ATP-binding site of Hsp90 and stabilized the inactive “open” or “lid-up” conformation as evidenced by molecular dynamic simulation. Furthermore, taxifolin was found to bind to interface of Hsp90 and Cdc37 complex and disrupt the interaction of residues of both proteins which were essential for the formation of active super-chaperone complex. Thus, taxifolin was found to act as an inhibitor of chaperoning process and may play a potential role in the cancer chemotherapeutics.

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► Docking of taxifolin to ATP-binding site of Hsp90 and stability evaluation of complex by molecular dynamic simulation.
► Molecular mechanism of inhibition of Hsp90 by taxifolin and induced conformational changes.
► Binding of taxifolin to Hsp90–cdc37 complex interface and effect of binding on the Hsp90–cdc37 interface residue interaction.