Structural and functional aspects of P-glycoproteins and related transport proteins.
The emergence of multidrug resistance in tumor cells is caused by the expression of P-glycoprotein. P-glycoprotein has a unique structure formed by two homologous halves, each encoding six putative transmembrane segments and one nucleotide binding fold. This structural arrangement has been conserved in a large number of eukaryotic and prokaryotic membrane transport systems, which together form the ATP binding cassette superfamily. These membrane transporters act on different groups of substrates in different cell types and organisms. The combined molecular analysis of these proteins has shed light on the mechanism by which P-glycoprotein acts on structurally unrelated groups of chemotherapeutic drugs and has allowed the identification of the protein domain responsible for the common mechanism of transport and recognition of substrate molecules. The function of P-glycoprotein in normal tissues remains intriguing and is discussed in this review.
Lepage
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Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Gros
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D018432:Drug Resistance, Multiple / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C505032:CFTR protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator