The Remarkable Transport Mechanism of P-Glycoprotein: A Multidrug Transporter |
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Authors: | Marwan K Al-Shawi Hiroshi Omote |
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Institution: | (1) Department of Molecular Physiology and Biological Physics, University of Virginia Health System, P.O. Box 800736, Charlottesville, Virginia, 22908-0736;(2) Present address: Department of Membrane Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Okayama 700-8520, Japan |
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Abstract: | Human P-glycoprotein (ABCB1) is a primary multidrug transporter located in plasma membranes, that utilizes the energy of ATP
hydrolysis to pump toxic xenobiotics out of cells. P-glycoprotein employs a most unusual molecular mechanism to perform this
drug transport function. Here we review our work to elucidate the molecular mechanism of drug transport by P-glycoprotein.
High level heterologous expression of human P-glycoprotein, in the yeast Saccharomyces cerevisiae, has facilitated biophysical studies in purified proteoliposome preparations. Development of novel spin-labeled transport
substrates has allowed for quantitative and rigorous measurements of drug transport in real time by EPR spectroscopy. We have
developed a new drug transport model of P-glycoprotein from the results of mutagenic, quantitative thermodynamic and kinetic
studies. This model satisfactorily accounts for most of the unusual kinetic, coupling, and physiological features of P-glycoprotein.
Additionally, an atomic detail structural model of P-glycoprotein has been devised to place our results within a proper structural
context. |
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Keywords: | P-glycoprotein multidrug resistance transporter energy coupling mechanism thermodynamics kinetics EPR homology modeling heterologous expression |
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