Identification of an inhibitor of hsc70-mediated protein translocation and ATP hydrolysis

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