Identification of an inhibitor of hsc70-mediated protein translocation andATP hydrolysis

Members of the hsc70 family of molecular chaperones are critical players in the folding and quality control of cellular proteins, Because several huma n diseases arise from defects in protein folding, the activity of hsc70 cha perones is a potential therapeutic target for these disorders, By using a k nown hsc70 modulator, 15-deoxyspergualin, as a seed, we identified a novel inhibitor of hsc70 activity. This compound, R/1, inhibits the endogenous an d DnaJ-stimulated ATPase activity of hsc70 by 48 and 51%, respectively, and blocks the hsc70-mediated translocation of a preprotein into yeast endopla smic reticulum-derived microsomal vesicles. Biochemical studies demonstrate that WI most likely exerts these effects by altering the oligomeric state of hsc70.