New Insights into the Drug Binding,Transport and Lipid Flippase Activities of the P-Glycoprotein Multidrug Transporter |
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Authors: | Email author" target="_blank">Frances?J?SharomEmail author Miguel?R?Lugo Paul?D?W?Eckford |
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Institution: | (1) Department of Molecular and Cellular Biology, University of Guelph, Science Complex Room 2255, Guelph, Ontario, Canada, N1G 2W1;(2) Instituto de Biología Experimental, Facultad de Ciencias, Universidad Central de Venezuela, Caracas, Venezuela |
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Abstract: | The MDR1 P-glycoprotein, an ATP-binding cassette (ABC) superfamily member that functions as an ATP-driven drug efflux pump,
has been linked to resistance of human tumors to multiple chemotherapeutic agents. P-glycoprotein binds and actively transports
a large variety of hydrophobic drugs and peptides. P-glycoprotein in reconstituted proteoliposomes is also an outwardly directed
flippase for membrane phospholipids and simple glycosphinglipids. This review focuses on recent advances in our understanding
of P-glycoprotein structure and function, particularly through the use of fluorescence spectroscopic approaches. Progress
is being made towards understanding the structure of the transporter, especially the spatial relationship between the two
nucleotide-binding domains. Exploration of the P-glycoprotein catalytic cycle using vanadate-trapped complexes has revealed
that drug transport likely takes place by concerted conformational changes linked to relaxation of a high energy intermediate.
Low resolution mapping of the protein using fluorescence resonance energy transfer showed that both the H and R drug-binding
sites are located within the cytoplasmic leaflet. Two drugs can bind to the R-site simultaneously, suggesting that the protein
contains a large flexible binding region. |
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Keywords: | ABC transporter P-glycoprotein MDR1 multidrug resistance reconstitution lipid bilayers fluorescence spectroscopy drug binding lipid flippase glycosphingolipid |
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