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New Insights into the Drug Binding, Transport and Lipid Flippase Activities of the P-Glycoprotein Multidrug Transporter

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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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Abbreviations

ABC:

ATP-binding cassette

FRET:

fluorescence resonance energy transfer

GlcCer:

glycosylceramide

LDS-751:

2-[4-(4-[dimethylamino]phenyl)-1,3-butadienyl]-3-ethylbenzo-thiazolium perchlorate

MIANS:

2-(4-maleimidoanilino)naphthalene-6-sulfonic acid

NB:

nucleotide binding

NBD:

nitrobenzo-2-oxa-1,3-diazole

PC:

phosphatidylcholine

R123:

rhodamine 123

TM:

transmembrane

TMR:

tetramethylrosamine

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Correspondence to Frances J. Sharom.

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Sharom, F.J., Lugo, M.R. & Eckford, P.D.W. New Insights into the Drug Binding, Transport and Lipid Flippase Activities of the P-Glycoprotein Multidrug Transporter. J Bioenerg Biomembr 37, 481–487 (2005). https://doi.org/10.1007/s10863-005-9496-6

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  • DOI: https://doi.org/10.1007/s10863-005-9496-6

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