Journal
JOURNAL OF BIOENERGETICS AND BIOMEMBRANES
Volume 37, Issue 6, Pages 489-496Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10863-005-9497-5
Keywords
P-glycoprotein; multidrug resistance; transporter; energy coupling; mechanism; thermodynamics; kinetics; EPR; homology modeling; heterologous expression
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Funding
- NIGMS NIH HHS [GM52502, R01 GM052502-09A1, R01 GM052502] Funding Source: Medline
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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 10 place Our results within a proper structural context.
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