INTERACTION OF PRENYLCYSTEINE METHYL-ESTERS WITH THE MULTIDRUG-RESISTANCE TRANSPORTER

The multidrug resistance transporter is an integral membrane protein, termed P-glycoprotein, which can function as an ATP dependent drug eff lux pump to reduce intracellular drug accumulation in treated cells. T he physiologic function of this protein in normal cells, however, is n ot completely understood. We report here that prenylcysteine methyl es ters, which represent the C-terminal structures of prenylated proteins , both stimulate the transporter's intrinsic ATPase activity and compe te for drug binding. The structural elements of prenylcysteine methyl esters involved in their interaction with P-glycoprotein include the i soprenoid moiety, the carboxyl methyl group, and the free amino group. These findings indicate that these molecules are potential physiologi c ligands of the transporter. Furthermore, as the structures of the ac tive prenylcysteines are distinct from the known substrates of P-glyco protein, this information may facilitate design of novel inhibitors of the transporter.