Journal of Bioenergetics and Biomembranes

, Volume 37, Issue 6, pp 489–496 | Cite as

The Remarkable Transport Mechanism of P-Glycoprotein: A Multidrug Transporter

  • Marwan K. Al-Shawi
  • Hiroshi Omote


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.

Key Words

P-glycoprotein multidrug resistance transporter energy coupling mechanism thermodynamics kinetics EPR homology modeling heterologous expression 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Al-Shawi, M. K., Polar, M. K., Omote, H., and Figler, R. A. (2003). J. Biol. Chem. 278, 52629–52640.CrossRefGoogle Scholar
  2. Al-Shawi, M. K., and Senior, A. E. (1993). J. Biol. Chem. 268, 4197–4206.Google Scholar
  3. Ambudkar, S. V., Dey, S., Hrycyna, C. A., Ramachandra, M., Pastan, I., and Gottesman, M. M. (1999). Annu. Rev. Pharmacol. Toxicol. 39, 361–398.CrossRefGoogle Scholar
  4. Chang, G. (2003). J. Mol. Biol. 330, 419–430.CrossRefGoogle Scholar
  5. Chang, G., and Roth, C. B. (2001). Science 293, 1793–1800.CrossRefGoogle Scholar
  6. Choi, K. H., Chen, C. J., Kriegler, M., and Roninson, I. B. (1988). Cell 53, 519–529.CrossRefGoogle Scholar
  7. Davidson, A. L., and Chen, J. (2004). Annu. Rev. Biochem. 73, 241–268.CrossRefGoogle Scholar
  8. De Rivoyre, M., Bonino, F., Ruel, L., Bidet, M., Therond, P., and Mus-Veteau, I. (2005). FEBS Lett. 579, 1529–1533.CrossRefGoogle Scholar
  9. Ecker, G., Huber, M., Schmid, D., and Chiba, P. (1999). Mol. Pharmacol. 56, 791–796.Google Scholar
  10. Exner, O. (1973). Prog. Phys. Org. Chem. 10, 411–482.Google Scholar
  11. Figler, R. A., Omote, H., Nakamoto, R. K., and Al-Shawi, M. K. (2000). Arch. Biochem. Biophys. 376, 34–46.CrossRefGoogle Scholar
  12. Flewelling, R. F., and Hubbell, W. L. (1986). Biophys. J. 49, 531–540.Google Scholar
  13. Gottesman, M. M., and Pastan, I. (1993). Annu. Rev. Biochem. 62, 385–427.CrossRefGoogle Scholar
  14. Holland, I. B., and Blight, M. A. (1999). J. Mol. Biol. 293, 381–399.CrossRefGoogle Scholar
  15. Hung, L. W., Wang, I. X., Nikaido, K., Liu, P. Q., Ames, G. F.-L., and Kim, S. H. (1998). Nature 396, 703–707.CrossRefGoogle Scholar
  16. Hyde, S. C., Emsley, P., Hartshorn, M. J., Mimmack, M. M., Gileadi, U., Pearce, S. R., Gallagher, M. P., Gill, D. R., Hubbard, R. E., and Higgins, C. F. (1990). Nature 346, 362–365.CrossRefGoogle Scholar
  17. Kioka, N., Tsubota, J., Kakehi, Y., Komano, T., Gottesman, M. M., Pastan, I., and Ueda, K. (1989). Biochem. Biophys. Res. Commun. 162, 224–231.CrossRefGoogle Scholar
  18. Lee, S. H., and Altenberg, G. A. (2003a). Biochem. Biophys. Res. Commun. 306, 644–649.CrossRefGoogle Scholar
  19. Lee, S. H., and Altenberg, G. A. (2003b). Biochem. J. 370, 357–360.CrossRefGoogle Scholar
  20. Leslie, E. M., Deeley, R. G., and Cole, S. P. (2005). Toxicol. Appl. Pharmacol. 204, 216–237.CrossRefGoogle Scholar
  21. Litman, T., Skovsgaard, T., and Stein, W. D. (2003). J. Pharmacol. Exp. Ther. 307, 846–853.CrossRefGoogle Scholar
  22. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004a). J. Biol. Chem. 279, 7692–7697.CrossRefGoogle Scholar
  23. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004b). J. Biol. Chem. 279, 18232–18238.CrossRefGoogle Scholar
  24. Moiseenkova, V. Y., Hellmich, H. L., and Christensen, B. N. (2003). Biochem. Biophys. Res. Commun. 310, 196–201.CrossRefGoogle Scholar
  25. Muller, M., Bakos, E., Welker, E., Varadi, A., Germann, U. A., Gottesman, M. M., Morse, B. S., Roninson, I. B., and Sarkadi, B. (1996). J. Biol. Chem. 271, 1877–1883.CrossRefGoogle Scholar
  26. Nakamoto, R. K., Ketchum, C. J., and Al-Shawi, M. K. (1999). Annu. Rev. Biophys. Biomol. Struct. 28, 205–234.CrossRefGoogle Scholar
  27. Omote, H., and Al-Shawi, M. K. (2002). J. Biol. Chem. 277, 45688–45694.CrossRefGoogle Scholar
  28. Omote, H., Figler, R. A., Polar, M. K., and Al-Shawi, M. K. (2004). Biochemistry 43, 3917–3928.CrossRefGoogle Scholar
  29. Pisani, D. F., Rivoyre, M. D., Ruel, L., Bonino, F., Bidet, M., Dechesne, C. A., and Mus-Veteau, I. (2005). Biochem. Biophys. Res. Commun. 331, 552–556.CrossRefGoogle Scholar
  30. Polgar, O., and Bates, S. E. (2005). Biochem. Soc. Trans. 33, 241–245.CrossRefGoogle Scholar
  31. Ramachandra, M., Ambudkar, S. V., Gottesman, M. M., Pastan, I., and Hrycyna, C. A. (1996). Mol. Biol. Cell 7, 1485–1498.Google Scholar
  32. Ramachandran, G. N., and Sasisekharan, V. (1968). Adv. Protein. Chem. 23, 283–438.CrossRefGoogle Scholar
  33. Rao, U. S. (1995). J. Biol. Chem. 270, 6686–6690.CrossRefGoogle Scholar
  34. Rao, U. S., and Nuti, S. L. (2003). J. Biol. Chem. 278, 46576–46582.CrossRefGoogle Scholar
  35. Romsicki, Y., and Sharom, F. J. (1999). Biochemistry 38, 6887–6896.CrossRefGoogle Scholar
  36. Ruth, A., Stein, W. D., Rose, E., and Roninson, I. B. (2001). Biochemistry 40, 4332–4339.CrossRefGoogle Scholar
  37. Safa, A. R., Stern, R. K., Choi, K., Agresti, M., Tamai, I., Mehta, N. D., and Roninson, I. B. (1990). Proc. Natl. Acad. Sci. USA 87, 7225–7229.Google Scholar
  38. Sauna, Z. E., and Ambudkar, S. V. (2001). J. Biol. Chem. 276, 11653–11661.CrossRefGoogle Scholar
  39. Seelig, A. (1998). Eur. J. Biochem. 251, 252–261.CrossRefGoogle Scholar
  40. Seelig, A., Blatter, X. L., and Wohnsland, F. (2000). Int. J. Clin. Pharmacol. Ther. 38, 111–121.Google Scholar
  41. Seelig, A., and Landwojtowicz, E. (2000). Eur. J. Pharm. Sci. 12, 31– 40.CrossRefGoogle Scholar
  42. Senior, A. E., Al-Shawi, M. K., and Urbatsch, I. L. (1995a). FEBS Lett. 377, 285–289.CrossRefGoogle Scholar
  43. Senior, A. E., Al-Shawi, M. K., and Urbatsch, I. L. (1995b). J. Bioenerg. Biomembr. 27, 31–36.CrossRefGoogle Scholar
  44. Shapiro, A. B., Corder, A. B., and Ling, V. (1997). Eur. J. Biochem. 250, 115–121.CrossRefGoogle Scholar
  45. Shapiro, A. B., Fox, K., Lam, P., and Ling, V. (1999). Eur. J. Biochem. 259, 841–850.CrossRefGoogle Scholar
  46. Shapiro, A. B., and Ling, V. (1995). J. Biol. Chem. 270, 16167–16175.CrossRefGoogle Scholar
  47. Shapiro, A. B., and Ling, V. (1997a). Eur. J. Biochem. 250, 122–129.CrossRefGoogle Scholar
  48. Shapiro, A. B., and Ling, V. (1997b). Eur. J. Biochem. 250, 130–137.CrossRefGoogle Scholar
  49. Shapiro, A. B., and Ling, V. (1998). Eur. J. Biochem. 254, 181–188.CrossRefGoogle Scholar
  50. Sharom, F. J. (1997). J. Membr. Biol. 160, 161–175.CrossRefGoogle Scholar
  51. Sharom, F. J., Yu, X., and Doige, C. A. (1993). J. Biol. Chem. 268, 24197–24202.Google Scholar
  52. Shilling, R. A., Balakrishnan, L., Shahi, S., Venter, H., and van Veen, H. W. (2003). Int. J. Antimicrob. Agents 22, 200–204.CrossRefGoogle Scholar
  53. Stein, W. D., Cardarelli, C., Pastan, I., and Gottesman, M. M. (1994). Mol. Pharmacol. 45, 763–772.Google Scholar
  54. Stenham, D. R., Campbell, J. D., Sansom, M. S., Higgins, C. F., Kerr, I. D., and Linton, K. J. (2003). FASEB J. 17, 2287–2289.Google Scholar
  55. Tu, B. P., and Weissman, J. S. (2002). Mol. Cell. 10, 983–994.CrossRefGoogle Scholar
  56. Urbatsch, I. L., Al-Shawi, M. K., and Senior, A. E. (1994). Biochemistry 33, 7069–7076.CrossRefGoogle Scholar
  57. Victor, K. G., and Cafiso, D. S. (2001). Biophys. J. 81, 2241–2250.CrossRefGoogle Scholar
  58. Yusa, K., and Tsuruo, T. (1989). Cancer Res. 49, 5002–5006.Google Scholar
  59. Zeng, G. F., Pypaert, M., and Slayman, C. L. (2004). J. Biol. Chem. 279, 3003–3013.CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Marwan K. Al-Shawi
    • 1
  • Hiroshi Omote
    • 1
    • 2
  1. 1.Department of Molecular Physiology and Biological PhysicsUniversity of Virginia Health SystemCharlottesville
  2. 2.Department of Membrane Biochemistry, Faculty of Pharmaceutical SciencesOkayama UniversityOkayamaJapan

Personalised recommendations