title: Interaction of prenylcysteine methyl esters with the multidrug resistance transporter.
abstract: The multidrug resistance transporter is an integral membrane protein, termed P-glycoprotein, which can function as an ATP-dependent drug efflux pump to reduce intracellular drug accumulation in treated cells. The physiologic function of this protein in normal cells, however, is not completely understood. We report here that prenylcysteine methyl esters, which represent the C-terminal structures of prenylated proteins, both stimulate the transporter's intrinsic ATPase activity and compete for drug binding. The structural elements of prenylcysteine methyl esters involved in their interaction with P-glycoprotein include the isoprenoid moiety, the carboxyl methyl group, and the free amino group. These findings indicate that these molecules are potential physiologic ligands of the transporter. Furthermore, as the structures of the active prenylcysteines are distinct from the known substrates of P-glycoprotein, this information may facilitate design of novel inhibitors of the transporter.
authors.affiliation: Department of Molecular Cancer Biology and Biochemistry, Durham Veterans Administration Medical Center, North Carolina.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: C W
authors.initials: CW
authors.lastname: Sachs
authors.forename: R L
authors.initials: RL
authors.lastname: Fine
authors.forename: P J
authors.initials: PJ
authors.lastname: Casey
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology; D004952:Esters / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009036:Moths / Q000166:cytology; D017368:Protein Prenylation; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D013729:Terpenes / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D004224:Diterpenes; D004952:Esters; D008024:Ligands; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D013729:Terpenes; C065977:geranylgeranylcysteine; C057785:S-farnesylcysteine; D000251:Adenosine Triphosphatases; D003545:Cysteine