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Journal of Bioenergetics and Biomembranes

, Volume 37, Issue 6, pp 489–496 | Cite as

The Remarkable Transport Mechanism of P-Glycoprotein: A Multidrug Transporter

  • Marwan K. Al-Shawi
  • Hiroshi Omote
Article

 

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.

Key Words

P-glycoprotein multidrug resistance transporter energy coupling mechanism thermodynamics kinetics EPR homology modeling heterologous expression 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Marwan K. Al-Shawi
    • 1
  • Hiroshi Omote
    • 1
    • 2
  1. 1.Department of Molecular Physiology and Biological PhysicsUniversity of Virginia Health SystemCharlottesville
  2. 2.Department of Membrane Biochemistry, Faculty of Pharmaceutical SciencesOkayama UniversityOkayamaJapan

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