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.
Original language | English |
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Pages (from-to) | 489-496 |
Number of pages | 8 |
Journal | Journal of Bioenergetics and Biomembranes |
Volume | 37 |
Issue number | 6 |
DOIs | |
Publication status | Published - Dec 2005 |
Keywords
- EPR
- Energy coupling
- Heterologous expression
- Homology modeling
- Kinetics
- Mechanism
- Multidrug resistance
- P-glycoprotein
- Thermodynamics
- Transporter
ASJC Scopus subject areas
- Physiology
- Cell Biology