P glycoprotein and the Mechanism of Multidrug Resistance

  1. Gregory Bock and
  2. Jamie A. Goode
  1. András Váradi1,
  2. Gergely Szakács2,
  3. Éva Bakos1 and
  4. Balázs Sarkadi2

Published Online: 7 OCT 2008

DOI: 10.1002/0470846356.ch5

Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243

Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243

How to Cite

Váradi, A., Szakács, G., Bakos, É. and Sarkadi, B. (2002) P glycoprotein and the Mechanism of Multidrug Resistance, in Mechanisms of Drug Resistance in Epilepsy: Novartis Foundation Symposium 243 (eds G. Bock and J. A. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470846356.ch5

Author Information

  1. 1

    Institute of Enzymology, Hungarian Academy of Sciences, Karolina ut 29, Budapest H-1113, Hungary

  2. 2

    National Institute of Hematology and Immunology, Membrane Research Group of SEB-Hungarian Academy of Science, Daróczi ut 24, Budapest H-1113, Hungary

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 25 MAR 2002

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470841464

Online ISBN: 9780470846353

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Summary

The human P glycoprotein (Pgp; MDR1) is an ATP-driven transporter for hydrophobic drugs and causes multidrug resistance in cancer. Our knowledge related to the mechanistic details of the ATP hydrolytic cycle of MDR1 has recently significantly progressed due to studies on the formation of a catalytic intermediate (occluded nucleotide state). According to the most accepted current model, both catalytic sites in MDR1 are active and ATP is hydrolysed alternatively within the two sites. ATP hydrolysis at one site triggers conformational changes within the protein resulting in drug transport, while hydrolysis of a second ATP molecule (at the other site) is required for resetting the initial (‘high-affinity binding’) conformation. The two active sites act in a cooperative manner and experiments support a model where the two ATP binding cassette (ABC) domains form a coupled catalytic machinery. Although no high resolution structure is available as yet, some relevant structural information can be deduced from crystal structures obtained for several bacterial ABC units, and the recently solved bacterial ABC–ABC dimer crystal structures may provide the basis for a better understanding of the intramolecular cross-talk between the two catalytic sites. As intramolecular interactions between various domains of Pgp/MDR1 are essential in regulating both the ATPase and transport activity, compounds perturbing these interactions may interfere with the function of the transporter. Such compounds, as well as various substrate analogues may be useful in modulating multidrug resistance in cancer.