22] Identification of drug interaction sites in P-glycoprotein

Abstract

Publisher Summary This chapter discusses the identification of drug interaction sites in P-glycoprotein that behaves as an energy-dependent efflux pump capable of transporting structurally diverse anticancer drugs, such as taxol, vinblastine, doxorubicin, and etoposide. When the protein is overexpressed, as it is in drug-selected cells, or in some tumors, multiple drug resistance (MDR) can occur. Agents that bind to P-glycoprotein and block the transport of anticancer drugs can re-sensitize MDR cells to chemotherapy and may have clinical utility. Each cassette contains six putative transmembrane (TM) domains, followed by an adenosine triphosphate (ATP)-binding motif. P-glycoprotein belongs to a large family, known as “ATP-binding cassette (ABC) transporters,” which in mammalian systems contains either the two cassettes linked in tandem or one cassette that is likely to operate as a dimer. ABC transporters allow the movement of small molecules including peptides, ions, and drugs through the membrane. Because structural conservation exists, it seems likely that ABC transporters share common mechanistic properties with specialization for individual ligands and methods have utility beyond P-glycoprotein.