A NEW STRUCTURAL MODEL FOR P-GLYCOPROTEIN

Multidrug resistance to anti-cancer drugs is a major medical problem. Resistance is manifested largely by the product of the human MDR1 gene , P-glycoprotein, an ABC transporter that is an integral membrane prot ein of 1280 amino acids arranged into two homologous halves, each comp rising 6 putative transmembrane alpha-helices and an ATP binding domai n. Despite the plethora of data from site-directed, scanning and domai n replacement mutagenesis, epitope mapping and photoaffinity labeling, a clear structural model for P-glycoprotein remains largely elusive. In this report, we propose a new model for P-glycoprotein that is supp orted by the vast body of previous data. The model comprises 2 membran e-embedded 16-strand beta-barrels, attached by short loops to two 6-he lix bundles beneath each barrel. Each ATP binding domain contributes 2 beta-strands and 1 alpha-helix to the structure. This model, together with an analysis of the amino acid sequence alignment of P-glycoprote in isoforms, is used to delineate drug binding and translocation sites . We show that the locations of these sites are consistent with mutati onal, kinetic and labeling data.