MOLECULAR ANALYSIS OF THE MULTIDRUG TRANSPORTER

The multidrug resistance gene product, P-glycoprotein or the multidrug transporter, confers multidrug resistance to cancer cells by maintain ing intracellular levels of cytotoxic agents below a killing threshold . P-glycoprotein is located within the plasma membrane and is thought to act as an energy-dependent drug efflux pump. The multidrug transpor ter represents a member of the ATP-binding cassette superfamily of tra nsporters (or traffic ATPases) and is composed of two highly homologou s halves, each of which harbors a hydrophobic transmembrane domain and a hydrophilic ATP-binding fold. This review focuses on various bioche mical and molecular genetic approaches used to analyze the structure, function, and mechanism of action of the multidrug transporter, whose most intriguing feature is its ability to interact with a large number of structurally and functionally different amphiphilic compounds. The se studies have underscored the complexity of this membrane protein wh ich has recently been suggested to assume alternative topological and quaternary structures, and to serve multiple functions both as a trans porter and as a channel. With respect to the multidrug transporter act ivity of P-glycoprotein, progress has been made towards the elucidatio n of essential amino acid residues and/or polypeptide regions. Further more, the drug-stimulatable ATPase activity of P-glycoprotein has been established. The mechanism of drug transport by P-glycoprotein, howev er, is still unknown and its physiological role remains a matter of sp eculation.