A New Structural Model for P-Glycoprotein |
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Authors: | PM Jones AM George |
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Institution: | (1) Department of Cell and Molecular Biology, University of Technology Sydney, Sydney, NSW 2007, Australia, AU |
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Abstract: | 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 protein of 1280 amino acids arranged into two homologous
halves, each comprising 6 putative transmembrane α-helices and an ATP binding domain. Despite the plethora of data from site-directed,
scanning and domain 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 supported by the vast body of previous
data. The model comprises 2 membrane-embedded 16-strand β-barrels, attached by short loops to two 6-helix bundles beneath
each barrel. Each ATP binding domain contributes 2 β-strands and 1 α-helix to the structure. This model, together with an
analysis of the amino acid sequence alignment of P-glycoprotein isoforms, is used to delineate drug binding and translocation
sites. We show that the locations of these sites are consistent with mutational, kinetic and labeling data.
Received: 18 February 1998/Revised: 2 September 1998 |
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Keywords: | : P-glycoprotein — Membrane topology — Multidrug resistance — β -barrel — ABC transporter |
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