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 |
|---|---|
| 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 |
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Keywords
- Energy coupling
- EPR
- Heterologous expression
- Homology modeling
- Kinetics
- Mechanism
- Multidrug resistance
- P-glycoprotein
- Thermodynamics
- Transporter
ASJC Scopus subject areas
- Physiology
- Cell Biology
Cite this
The remarkable transport mechanism of P-glycoprotein : A multidrug transporter. / Al-Shawi, Marwan K.; Omote, Hiroshi.
In: Journal of Bioenergetics and Biomembranes, Vol. 37, No. 6, 12.2005, p. 489-496.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The remarkable transport mechanism of P-glycoprotein
T2 - A multidrug transporter
AU - Al-Shawi, Marwan K.
AU - Omote, Hiroshi
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
KW - Energy coupling
KW - EPR
KW - Heterologous expression
KW - Homology modeling
KW - Kinetics
KW - Mechanism
KW - Multidrug resistance
KW - P-glycoprotein
KW - Thermodynamics
KW - Transporter
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UR - http://www.scopus.com/inward/citedby.url?scp=33646596002&partnerID=8YFLogxK
U2 - 10.1007/s10863-005-9497-5
DO - 10.1007/s10863-005-9497-5
M3 - Article
VL - 37
SP - 489
EP - 496
JO - Journal of Bioenergetics and Biomembranes
JF - Journal of Bioenergetics and Biomembranes
SN - 0145-479X
IS - 6
ER -