Molecular Mechanism of Inhibition of the Human Protein Complex Hsp90–Cdc37, a Kinome Chaperone–Cochaperone, by Triterpene Celastrol

The correct target: The cell division cycle protein 37 (Cdc37) and the heat shock protein (Hsp90) are molecular chaperones crucial for the folding and stabilization of protein kinases including the oncogenic kinases. NMR studies show that celastrol, a recently identified triterpene targeting Hsp90, in fact binds to Cdc37 and disrupts the Cdc37–Hsp90 complex. Celastrol inactivates Cdc37 through a thiol-mediated mechanism.