Journal of Bioenergetics and Biomembranes

, Volume 37, Issue 6, pp 481–487

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

  • Frances J. Sharom
  • Miguel R. Lugo
  • Paul D. W. Eckford
Article

DOI: 10.1007/s10863-005-9496-6

Cite this article as:
Sharom, F.J., Lugo, M.R. & Eckford, P.D.W. J Bioenerg Biomembr (2005) 37: 481. doi:10.1007/s10863-005-9496-6

 

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.

Key Words

ABC transporter P-glycoprotein MDR1 multidrug resistance reconstitution lipid bilayers fluorescence spectroscopy drug binding lipid flippase glycosphingolipid 

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

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Frances J. Sharom
    • 1
  • Miguel R. Lugo
    • 2
  • Paul D. W. Eckford
    • 1
  1. 1.Department of Molecular and Cellular BiologyUniversity of GuelphGuelphCanada
  2. 2.Instituto de Biología Experimental, Facultad de CienciasUniversidad Central de VenezuelaCaracasVenezuela

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