Skip to main content
Log in

Structure and Function of Multidrug Resistance Protein 1

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

This review considers one of the most clinically relevant representatives of the ABC transporters–multidrug resistance protein 1 (P-glycoprotein 1 or Pgp). Data on the primary, secondary, and tertiary structure of the protein, its synthesis and degradation, and roles of its fragments in transporter activity are presented. Particular attention is given to the mechanism of functioning of Pgp. In view of the absence of a generally recognized mechanism of action of Pgp, several existing models of the protein transport cycle are discussed. Epigenetic regulation of the ABCB1 gene and modulation of Pgp expression by microRNAs are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vasiliou, V., Vasiliou, K., and Nebert, D. W. (2009) Human ATP–binding cassette (ABC) transporter family, Hum. Genomics, 3, 281–290.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Higgins, C. F. (1992) ABC transporters: from microorganisms to man, Annu. Rev. Cell Biol., 8, 67–113.

    Article  PubMed  CAS  Google Scholar 

  3. Dean, M., Hamon, Y., and Chimini, G. (2001) The human ATP–binding cassette (ABC) transporter superfamily, J. Lipid Res., 42, 1007–1017.

    PubMed  CAS  Google Scholar 

  4. Fletcher, J. I., Haber, M., Henderson, M. J., and Norris, M. D. (2010) ABC transporters in cancer: more than just drug efflux pumps, Nat. Rev. Cancer, 10, 147–156.

    Article  PubMed  CAS  Google Scholar 

  5. Fletcher, J. I., Williams, R. T., Henderson, M. J., Norris, M. D., and Haber, M. (2016) ABC transporters as mediators of drug resistance and contributors to cancer cell biology, Drug Resist. Updat., 26, 1–9.

    Article  PubMed  Google Scholar 

  6. HGNC Database, HUGO Gene Nomenclature Committee (HGNC), European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK, URL, https://www.genenames.org/cgi-bin/genefamilies/set/417.

  7. The Universal Protein Resource (UniProt), URL, http://www.uniprot.org/uniprot/P08183.

  8. Stavrovskaya, A. A., and Stromskaya, T. P. (2008) Transport proteins of the ABC family and multidrug resistance of tumor cells, Biochemistry (Moscow), 73, 592–604.

    Article  CAS  Google Scholar 

  9. Becker, J. P., Depret, G., Van Bambeke, F., Tulkens, P. M., and Prevost, M. (2009) Molecular models of human P–glycoprotein in two different catalytic states, BMC Struct. Biol., 9, 1.

    Article  CAS  Google Scholar 

  10. Quazi, F., Lenevich, S., and Molday, R. S. (2012) ABCA4 is an N–retinylidene–phosphatidylethanolamine and phosphatidylethanolamine importer, Nat. Commun., 3, 925.

    Article  PubMed  CAS  Google Scholar 

  11. Zheleznova, E. E., Markham, P. N., Neyfakh, A. A., and Brennan, R. G. (1999) Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter, Cell, 96, 353–362.

    Article  PubMed  CAS  Google Scholar 

  12. Neifakh, A. A. (2003) Multiple drug resistance: solution for the problem? Biol. Membr. Zh. Membr. Klet. Biol., 20, 206–212.

    Google Scholar 

  13. Callen, D. F., Baker, E., Simmers, R. N., Seshadri, R., and Roninson, I. B. (1987) Localisation of the human multiple drug resistance gene, MDR1, to 7q21.1, Hum. Genet., 77, 142–144.

    Article  PubMed  CAS  Google Scholar 

  14. Brambila–Tapia, A. J. (2013) MDR1 (ABCB1) polymorphisms: functional effects and clinical implications, Rev. Invest. Clin., 65, 445–454.

    PubMed  Google Scholar 

  15. Szollosi, D., Rose–Sperling, D., Hellmich, U. A., and Stockner, T. (2018) Comparison of mechanistic transport cycle models of ABC exporters, Biochim. Biophys. Acta, 1860, 818–832.

    Article  CAS  Google Scholar 

  16. Ruetz, S., and Gros, P. (1994) Phosphatidylcholine translocase: a physiological role for the mdr 2 gene, Cell, 77, 1071–1081.

    Article  PubMed  CAS  Google Scholar 

  17. Van Helvoort, A., Smith, A. J., Sprong, H., Fritzsche, I., Schinkel, A. H., Borst, P., and van Meer, G. (1996) MDR1 P–glycoprotein is a lipid translocase of broad specificity, while MDR3 P–glycoprotein specifically translocates phosphatidylcholine, Cell, 87, 507–517.

    Article  PubMed  Google Scholar 

  18. Lin, J. H., and Yamazaki, M. (2003) Role of P–glycoprotein in pharmacokinetics: clinical implications, Clin. Pharmacokinet., 42, 59–98.

    Article  PubMed  CAS  Google Scholar 

  19. Smith, A. J., van Helvoort, A., van Meer, G., Szabo, K., Welker, E., Szakacs, G., Varadi, A., Sarkadi, B., and Borst, P. (2000) MDR3 P–glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping, J. Biol. Chem., 275, 23530–23539.

    Article  PubMed  CAS  Google Scholar 

  20. Loo, T. W., and Clarke, D. M. (1999) Determining the structure and mechanism of the human multidrug resistance P–glycoprotein using cysteine–scanning mutagenesis and thiol–modification techniques, Biochim. Biophys. Acta, 1461, 315–325.

    Article  PubMed  CAS  Google Scholar 

  21. Gribar, J. J., Ramachandra, M., Hrycyna, C. A., Dey, S., and Ambudkar, S. V. (2000) Functional characterization of glycosylation–deficient human P–glycoprotein using a vaccinia virus expression system, J. Membr. Biol., 173, 203–214.

    Article  PubMed  CAS  Google Scholar 

  22. Tang, Y., Beuerlein, G., Pecht, G., Chilton, T., Huse, W. D., and Watkins, J. D. (1999) Use of a peptide mimotope to guide the humanization of MRK–16, an anti–P–glycoprotein monoclonal antibody, J. Biol. Chem., 274, 27371–27378.

    Article  PubMed  CAS  Google Scholar 

  23. Germann, U. A. (1996) P–glycoprotein–a mediator of multidrug resistance in tumour cells, Eur. J. Cancer, 32, 927–944.

    Article  Google Scholar 

  24. Cohen, D., Yang, C.–P. H., and Horwitz, S. B. (1990) The products of the mdrla and mdrlb genes from multidrug resistant murine cells have similar degradation rates, Life Sci., 46, 489–495.

    Article  PubMed  CAS  Google Scholar 

  25. Juliano, R. L., and Ling, V. (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim. Biophys. Acta, 455, 152–162.

    Article  PubMed  CAS  Google Scholar 

  26. Borst, P., and Elferink, R. O. (2002) Mammalian ABC transporters in health and disease, Annu. Rev. Biochem., 71, 537–592.

    Article  PubMed  CAS  Google Scholar 

  27. Shilling, R. A., Venter, H., Velamakanni, S., Bapna, A., Woebking, B., Shahi, S., and van Veen, H. W. (2006) New light on multidrug binding by an ATP–binding–cassette transporter, Trends Pharmacol. Sci., 27, 195–203.

    Article  PubMed  CAS  Google Scholar 

  28. Li, Y., Yuan, H., Yang, K., Xu, W., Tang, W., and Li, X. (2010) The structure and functions of P–glycoprotein, Curr. Med. Chem., 17, 786–800.

    Article  PubMed  CAS  Google Scholar 

  29. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2005) The dileucine motif at the COOH terminus of human multidrug resistance P–glycoprotein is important for folding but not activity, J. Biol. Chem., 280, 2522–2528.

    Article  PubMed  CAS  Google Scholar 

  30. Kim, Y., and Chen, J. (2018) Molecular structure of human P–glycoprotein in the ATP–bound, outward–facing confor–mation, Science, 359, 915–919.

    Article  PubMed  CAS  Google Scholar 

  31. Kast, C., Canfield, V., Levenson, R., and Gros, P. (1995) Membrane topology of P–glycoprotein as determined by epitope insertion: transmembrane organization of the N–terminal domain of mdr3, Biochemistry, 34, 4402–4411.

    Article  PubMed  CAS  Google Scholar 

  32. Loo, T. W., and Clarke, D. M. (1995) Membrane topology of a cysteine–less mutant of human P–glycoprotein, J. Biol. Chem., 270, 843–848.

    Article  PubMed  CAS  Google Scholar 

  33. Loo, T. W., and Clarke, D. M. (2005) Do drug substrates enter the common drug–binding pocket of P–glycoprotein through gates? Biochem. Biophys. Res. Commun., 329, 419–422.

    Article  PubMed  CAS  Google Scholar 

  34. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2009) Identification of residues in the drug translocation pathway of the human multidrug resistance P–glycoprotein by arginine mutagenesis, J. Biol. Chem., 284, 24074–24087.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Dong, M., Ladaviere, L., Penin, F., Deleage, G., and Baggetto, L. G. (1998) Secondary structure of P–glycoprotein investigated by circular dichroism and amino acid sequence analysis, Biochim. Biophys. Acta, 1371, 317–334.

    Article  PubMed  CAS  Google Scholar 

  36. Hennessy, M., and Spiers, J. P. (2007) A primer on the mechanics of P–glycoprotein the multidrug transporter, Pharmacol. Res., 55, 1–15.

    Article  PubMed  CAS  Google Scholar 

  37. Nauck, M. A., El–Ouaghlidi, A., Gabrys, B., Hucking, K., Holst, J. J., Deacon, C. F., Gallwitz, B., Schmidt, W. E., and Meie, J. J. (2004) Secretion of incretin hormones (GIP and GLP–1) and incretin effect after oral glucose in first–degree relatives of patients with type 2 diabetes, Regul. Pept., 122, 209–217.

    Article  PubMed  CAS  Google Scholar 

  38. Rosenberg, M. F., Callaghan, R., Ford, R. C., and Higgins, C. F. (1997) Structure of the multidrug resistance P–glyco–protein to 2.5 nm resolution determined by electron microscopy and image analysis, J. Biol. Chem., 272, 10685–10694.

    Article  PubMed  CAS  Google Scholar 

  39. Rosenberg, M. F., Kamis, A. B., Callaghan, R., Higgins, C. F., and Ford, R. C. (2003) Three–dimensional structures of the mammalian multidrug resistance P–glycoprotein demonstrate major conformational changes in the trans–membrane domains upon nucleotide binding, J. Biol. Chem., 278, 8294–8299.

    Article  PubMed  CAS  Google Scholar 

  40. Rosenberg, M. F., Callaghan, R., Modok, S., Higgins, C. F., and Ford, R. C. (2005) Three–dimensional structure of P–glycoprotein: the transmembrane regions adopt an asym–metric configuration in the nucleotide–bound state, J. Biol. Chem., 280, 2857–2862.

    Article  PubMed  CAS  Google Scholar 

  41. Stenham, D. R., Campbell, J. D., Sansom, M. S., Higgins, C. F., Kerr, I. D., and Linton, K. J. (2003) An atomic detail model for the human ATP binding cassette transporter P–glycoprotein derived from disulfide cross–linking and homology modeling, Fed. Am. Soc. Exp. Biol., 17, 2287–2289.

    PubMed  CAS  Google Scholar 

  42. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004) Disulfide cross–linking analysis shows that transmembrane segments 5 and 8 of human P–glycoprotein are close together on the cytoplasmic side of the membrane, J. Biol. Chem., 279, 7692–7697.

    Article  PubMed  CAS  Google Scholar 

  43. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004) Val133 and Cys137 in transmembrane segment 2 are close to Arg935 and Gly939 in transmembrane segment 11 of human P–glycoprotein, J. Biol. Chem., 279, 18232–18238.

    Article  PubMed  CAS  Google Scholar 

  44. Al–Shawi, M. K., and Omote, H. (2005) The remarkable transport mechanism of P–glycoprotein: a multidrug transporter, J. Bioenerg. Biomembr., 37, 489–496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Pleban, K., Kopp, S., Csaszar, E., Peer, M., Hrebicek, T., Rizzi, A., Ecker, G. F., and Chiba, P. (2005) P–glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labeling–protein homology modeling approach, Mol. Pharmacol., 67, 365–374.

    Article  PubMed  CAS  Google Scholar 

  46. Loo, T. W., and Clarke, D. M. (1999) Molecular dissection of the human multidrug resistance P–glycoprotein, Biochem. Cell Biol., 77, 11–23.

    Article  PubMed  CAS  Google Scholar 

  47. Rothnie, A., Storm, J., McMahon, R., Taylor, A., Kerr, I. D., and Callaghan, R. (2005) The coupling mechanism of P–glycoprotein involves residue L339 in the sixth membrane spanning segment, FEBS Lett., 579, 3984–3990.

    Article  PubMed  CAS  Google Scholar 

  48. Loo, T. W., and Clarke, D. M. (1998) Superfolding of the partially unfolded core–glycosylated intermediate of human P–glycoprotein into the mature enzyme is promoted by substrate–induced transmembrane domain interactions, J. Biol. Chem., 273, 14671–14674.

    Article  PubMed  CAS  Google Scholar 

  49. Loo, T. W., and Clarke, D. M. (1999) The transmembrane domains of the human multidrug resistance P–glycoprotein are sufficient to mediate drug binding and trafficking to the cell surface, J. Biol. Chem., 274, 24759–24765.

    Article  PubMed  CAS  Google Scholar 

  50. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2005) ATP hydrolysis promotes interactions between the extracellular ends of transmembrane segments 1 and 11 of human multidrug resistance P–glycoprotein, Biochemistry, 44, 10250–10258.

    Article  PubMed  CAS  Google Scholar 

  51. Vigano, C., Julien, M., Carrier, I., Gros, P., and Ruysschaert, J. M. (2002) Structural and functional asymmetry of the nucleotide–binding domains of P–glycoprotein investigated by attenuated total reflection Fourier transform infrared spectroscopy, J. Biol. Chem., 277, 5008–5016.

    Article  PubMed  CAS  Google Scholar 

  52. Loo, T. W., and Clarke, D. M. (2001) Determining the dimensions of the drug–binding domain of human P–glyco–protein using thiol cross–linking compounds as molecular rulers, J. Biol. Chem., 276, 36877–36880.

    Article  PubMed  CAS  Google Scholar 

  53. Ambudkar, S. V., Kim, I. W., and Sauna, Z. E. (2006) The power of the pump: mechanisms of action of P–glycoprotein (ABCB1), Eur. J. Pharm. Sci., 27, 392–400.

    Article  PubMed  CAS  Google Scholar 

  54. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2003) Simultaneous binding of two different drugs in the binding pocket of the human multidrug resistance P–glycoprotein, J. Biol. Chem., 278, 39706–39710.

    Article  PubMed  CAS  Google Scholar 

  55. Loo, T. W., and Clarke, D. M. (2002) Location of the rhodamine–binding site in the human multidrug resistance P–glycoprotein, J. Biol. Chem., 277, 44332–44338.

    Article  PubMed  CAS  Google Scholar 

  56. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2003) Substrate–induced conformational changes in the transmembrane segments of human P–glycoprotein direct evidence for the substrate–induced fit mechanism for drug binding, J. Biol. Chem., 278, 13603–13606.

    Article  PubMed  CAS  Google Scholar 

  57. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2006) Transmembrane segment 1 of human P–glycoprotein contributes to the drug–binding pocket, Biochem. J., 396, 537–545.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Loo, T. W., and Clarke, D. M. (2001) Defining the drug–binding site in the human multidrug resistance P–glycoprotein using a methanethiosulfonate analog of verapamil, MTS–verapamil, J. Biol. Chem., 276, 14972–14979.

    Article  PubMed  CAS  Google Scholar 

  59. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2006) Transmembrane segment 7 of human P–glycoprotein forms part of the drug–binding pocket, Biochem. J., 399, 351–359.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Druley, T. E., Stein, W. D., Ruth, A., and Roninson, I. B. (2001) P–glycoprotein–mediated colchicine resistance in different cell lines correlates with the effects of colchicine on P–glycoprotein conformation, Biochemistry, 40, 4323–4331.

    Article  PubMed  CAS  Google Scholar 

  61. Lugo, M. R., and Sharom, F. J. (2005) Interaction of LDS–751 with P–glycoprotein and mapping of the location of the R drug binding site, Biochemistry, 44, 643–655.

    Article  PubMed  CAS  Google Scholar 

  62. Cianchetta, G., Singleton, R. W., Zhang, M., Wildgoose, M., Giesing, D., Fravolini, A., Cruciani, G., and Vaz, R. J. (2005) A pharmacophore hypothesis for P–glycoprotein substrate recognition using GRIND–based 3D–QSAR, J. Med. Chem., 48, 2927–2935.

    Article  PubMed  CAS  Google Scholar 

  63. Frelet, A., and Klein, M. (2006) Insight in eukaryotic ABC transporter function by mutation analysis, FEBS Lett., 580, 1064–1084.

    Article  PubMed  CAS  Google Scholar 

  64. Wan, C. K., Zhu, G. Y., Shen, X. L., Chattopadhyay, A., Dey, S., and Fong, W. F. (2006) Gomisin A alters substrate interaction and reverses P–glycoprotein–mediated mul–tidrug resistance in HepG2–DR cells, Biochem. Pharmacol., 72, 824–837.

    Article  PubMed  CAS  Google Scholar 

  65. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2002) The LSGGQ motif in each nucleotide–binding domain of human P–glycoprotein is adjacent to the opposing walker A sequence, J. Biol. Chem., 277, 41303–41306.

    Article  PubMed  CAS  Google Scholar 

  66. Li, W., Zhang, H., Assaraf, Y. G., Zhao, K., Xu, X., Xie, J., Yang, D. H., and Chen, Z. S. (2016) Overcoming ABC transporter–mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies, Drug Resist. Updat., 27, 14–29.

    Article  PubMed  CAS  Google Scholar 

  67. Kim, I. W., Peng, X. H., Sauna, Z. E., FitzGerald, P. C., Xia, D., Muller, M., Nandigama, K., and Ambudkar, S. V. (2006) The conserved tyrosine residues 401 and 1044 in ATP sites of human P–glycoprotein are critical for ATP binding and hydrolysis: evidence for a conserved subdomain, the A–loop in the ATP–binding cassette, Biochemistry, 45, 7605–7616.

    Article  PubMed  CAS  Google Scholar 

  68. Eytan, G. D., Regev, R., and Assaraf, Y. G. (1996) Functional reconstitution of P–glycoprotein reveals an apparent near stoichiometric drug transport to ATP hydrolysis, J. Biol. Chem., 271, 3172–3178.

    Article  PubMed  CAS  Google Scholar 

  69. Gottesman, M. M., Pastan, I., and Ambudkar, S. V. (1996) P–glycoprotein and multidrug resistance, Curr. Opin. Genet. Dev., 6, 610–617.

    Article  PubMed  CAS  Google Scholar 

  70. Sauna, Z. E., and Ambudkar, S. V. (2007) About a switch: how P–glycoprotein (ABCB1) harnesses the energy of ATP binding and hydrolysis to do mechanical work, Mol. Cancer Ther., 6, 13–23.

    Article  PubMed  CAS  Google Scholar 

  71. Sauna, Z. E., Nandigama, K., and Ambudka, S. V. (2006) Exploiting reaction intermediates of the ATPase reaction to elucidate the mechanism of transport by P–glycoprotein (ABCB1), J. Biol. Chem., 281, 26501–26511.

    Article  PubMed  CAS  Google Scholar 

  72. Tombline, G., Muharemagic, A., White, L. B., and Senior, A. F. (2005) Involvement of the occluded nucleotide conformation of P–glycoprotein in the catalytic pathway, Biochemistry, 44, 12879–12886.

    Article  PubMed  CAS  Google Scholar 

  73. Loo, T. W., and Clarke, D. M. (2001) Cross–linking of human multidrug resistance P–glycoprotein by the substrate, tris–(2–maleimidoethyl) amine, is altered by ATP hydrolysis evidence for rotation of a transmembrane helix, J. Biol. Chem., 276, 31800–31805.

    Article  PubMed  CAS  Google Scholar 

  74. Druley, T. E., Stein, W. D., Ruth, A., and Roninson, I. B. (2001) P–glycoprotein–mediated colchicine resistance in different cell lines correlates with the effects of colchicine on P–glycoprotein conformation, Biochemistry, 40, 4323–4331.

    Article  PubMed  CAS  Google Scholar 

  75. Ferte, J. (2000) Analysis of the tangled relationships between P–glycoprotein–mediated multidrug resistance and the lipid phase of the cell membrane, Eur. J. Biochem., 267, 277–294.

    Article  PubMed  CAS  Google Scholar 

  76. Hrycyna, C. A., Airan, L. E., Germann, U. A., Ambudkar, S. V., Pastan, I., and Gottesman, M. M. (1998) Structural flexibility of the linker region of human P–glycoprotein permits ATP hydrolysis and drug transport, Biochemistry, 37, 13660–13673.

    Article  PubMed  CAS  Google Scholar 

  77. Sharom, F. J., Yu, X., and Doige, C. A. (1993) Functional reconstitution of drug transport and ATPase activity in proteoliposomes containing partially purified P–glycoprotein, J. Biol. Chem., 268, 24197–24202.

    PubMed  CAS  Google Scholar 

  78. Ambudkar, S. V., Cardarelli, C. O., Pashinsky, I., and Stein, W. D. (1997) Relation between the turnover number for vinblastine transport and for vinblastine–stimulated ATP hydrolysis by human P–glycoprotein, J. Biol. Chem., 272, 21160–21166.

    Article  PubMed  CAS  Google Scholar 

  79. Shapiro, A. B., and Ling, V. (1998) Stoichiometry of cou–pling of rhodamine 123 transport to ATP hydrolysis by P–glycoprotein, Eur. J. Biochem., 254, 189–193.

    Article  PubMed  CAS  Google Scholar 

  80. Delannoy, S., Urbatsch, I. L., Tombline, G., Senior, A. E., and Vogel, P. D. (2005) Nucleotide binding to the mul–tidrug resistance P–glycoprotein as studied by ESR spectroscopy, Biochemistry, 44, 14010–14019.

    Article  PubMed  CAS  Google Scholar 

  81. Senior, A. E., Al–Shawi, M. K., and Urbatsch, I. L. (1995) The catalytic cycle of P–glycoprotein, FEBS Lett., 377, 285–289.

    Article  PubMed  CAS  Google Scholar 

  82. Urbatsch, I. L., Sankaran, B., Weber, J., and Senior, A. E. (1995) P–glycoprotein is stably inhibited by vanadate–induced trapping of nucleotide at a single catalytic site, J. Biol. Chem., 270, 19383–19390.

    Article  PubMed  CAS  Google Scholar 

  83. Urbatsch, I. L., Beaudet, L., Carrier, I., and Gros, P. (1998) Mutations in either nucleotide–binding site of P–glycoprotein (Mdr3) prevent vanadate trapping of nucleotide at both sites, Biochemistry, 37, 4592–4602.

    Article  PubMed  CAS  Google Scholar 

  84. Qu, Q., Russell, P. L., and Sharom, F. J. (2003) Stoichiometry and affinity of nucleotide binding to P–glycoprotein during the catalytic cycle, Biochemistry, 42, 1170–1177.

    Article  PubMed  CAS  Google Scholar 

  85. Wang, G., Pincheira, R., and Zhang, J. T. (1998) Dissection of drug–binding–induced conformational changes in P–glycoprotein, Eur. J. Biochem., 255, 383–390.

    Article  PubMed  CAS  Google Scholar 

  86. Julien, M., and Gros, P. (2000) Nucleotide–induced conformational changes in P–glycoprotein and in nucleotide binding site mutants monitored by trypsin sensitivity, Biochemistry, 39, 4559–4568.

    Article  PubMed  CAS  Google Scholar 

  87. Druley, T. E., Stein, W. D., and Roninson, I. B. (2001) Analysis of MDR1 P–glycoprotein conformational changes in permeabilized cells using differential immunoreactivity, Biochemistry, 40, 4312–4322.

    Article  PubMed  CAS  Google Scholar 

  88. Ruth, A., Stein, W. D., Rose, E., and Roninson, I. B. (2001) Coordinate changes in drug resistance and drug–induced conformational transitions in altered–function mutants of the multidrug transporter P–glycoprotein, Biochemistry, 40, 4332–4339.

    Article  PubMed  CAS  Google Scholar 

  89. Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2003) Drug binding in human P–glycoprotein causes conformational changes in both nucleotide–binding domains, J. Biol. Chem., 278, 1575–1578.

    Article  PubMed  CAS  Google Scholar 

  90. Callaghan, R., Ford, R. C., and Kerr, I. D. (2006) The translocation mechanism of P–glycoprotein, FEBS Lett., 580, 1056–1063.

    Article  PubMed  CAS  Google Scholar 

  91. Ambudkar, S. V., Kim, I. W., and Sauna, Z. E. (2006) The power of the pump: mechanisms of action of P–glycoprotein (ABCB1), Eur. J. Pharm. Sci., 27, 392–400.

    Article  PubMed  CAS  Google Scholar 

  92. Subramanian, N., Condic–Jurkic, K., and O’Mara, M. L. (2016) Structural and dynamic perspectives on the promis–cuous transport activity of P–glycoprotein, Neurochem. Int., 98, 146–152.

    Article  PubMed  CAS  Google Scholar 

  93. Martin, C., Higgins, C. F., and Callaghan, R. (2001) The vinblastine binding site adopts high–and low–affinity conformations during a transport cycle of P–glycoprotein, Biochemistry, 40, 15733–15742.

    Article  PubMed  CAS  Google Scholar 

  94. Rosenberg, M. F., Velarde, G., Ford, R. C., Martin, C., Berridge, G., Kerr, I. D., Callaghan, R., Schmidlin, A., Wooding, C., Linton, K. J., and Higgins, C. F. (2001) Repacking of the transmembrane domains of P–glycoprotein during the transport ATPase cycle, EMBO J., 20, 5615–5625.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Higgins, C. F., and Linton, K. J. (2004) The ATP switch model for ABC transporters, Nat. Struct. Mol. Biol., 11, 918–926.

    Article  PubMed  CAS  Google Scholar 

  96. 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) Structural model of ATP–binding protein associated with cystic fibrosis, multidrug resistance and bacterial transport, Nature, 26, 362–365.

    Article  Google Scholar 

  97. Mimura, C. S., Holbrook, S. R., and Ames, G. F. (1991) Structural model of the nucleotide–binding conserved component of periplasmic permeases, Proc. Natl. Acad. Sci. USA, 88, 84–88.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  98. Senior, A. E., Al–Shawi, M. K., and Urbatsch, I. L. (1995) The catalytic cycle of P–glycoprotein, FEBS Lett., 377, 285–289.

    Article  PubMed  CAS  Google Scholar 

  99. Al–Shawi, M. K., Polar, M. K., Omote, H., and Figler, R. A. (2003) Transition state analysis of the coupling of drug transport to ATP hydrolysis by P–glycoprotein, J. Biol. Chem., 278, 52629–52640.

    Article  PubMed  CAS  Google Scholar 

  100. Omote, H., and Al–Shawi, M. K. (2006) Interaction of transported drugs with the lipid bilayer and P–glycoprotein through a solvation exchange mechanism, Biophys. J., 90, 4046–4059.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Baker, E. K., Johnstone, R. W., Zalcberg, J. R., and El–Osta, A. (2005) Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs, Oncogene, 24, 8061–8075.

    Article  PubMed  CAS  Google Scholar 

  102. Chen, K. G., Wang, Y. C., Schaner, M. E., Francisco, B., Duran, G. E., Juric, D., Huff, L. M., Padilla–Nash, H., Ried, T., Fojo, T., and Sikic, B. I. (2005) Genetic and epigenetic modeling of the origins of multidrug–resistant cells in a human sarcoma cell line, Cancer Res., 65, 9388–9397.

    Article  PubMed  CAS  Google Scholar 

  103. Scotto, K. W. (2003) Transcriptional regulation of ABC drug transporters, Oncogene, 22, 7496–7511.

    Article  PubMed  CAS  Google Scholar 

  104. Ueda, K., Pastan, I., and Gottesman, M. M. (1987) Isolation and sequence of the promoter region of the human multidrug–resistance (P–glycoprotein) gene, J. Biol. Chem., 262, 17432–17436.

    PubMed  CAS  Google Scholar 

  105. Arrigoni, E., Galimberti, S., Petrini, M., Danesi, R., and Di Paolo, A. (2016) ATP–binding cassette transmembrane transporters and their epigenetic control in cancer: an overview, Expert Opin. Drug Metab. Toxicol., 12, 1419–1432.

    Article  PubMed  CAS  Google Scholar 

  106. Dejeux, E., Ronneberg, J. A., Solvang, H., Bukholm, I., Geisler, S., Aas, T., Gut, I. G., Borresen–Dale, A. L., Lonning, P. E., Kristensen, V. N., and Tost, J. (2010) DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response, Mol. Cancer, 9, 68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Mencalha, A. L., Rodrigues, E. F., Abdelhay, E., and Fernandez, T. S. (2013) Accurate monitoring of promoter gene methylation with high–resolution melting polymerase chain reaction using the ABCB1 gene as a model, Genet. Mol. Res., 12, 714–722.

    Article  PubMed  CAS  Google Scholar 

  108. Reed, K., Hembruff, S. L., Sprowl, J. A., and Parissenti, A. M. (2010) The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acqui–sition of drug resistance, Pharmacogenomics J., 10, 489–504.

    CAS  Google Scholar 

  109. Nakayama, M., Wada, M., Harada, T., Nagayama, J., Kusaba, H., Ohshima, K., Kozuru, M., Komatsu, H., Ueda, R., and Kuwano, M. (1998) Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias, Blood, 92, 4296–4307.

    PubMed  CAS  Google Scholar 

  110. Tada, Y., Wada, M., Kuroiwa, K., Kinugawa, N., Harada, T., Nagayama, J., Nakagawa, M., Naito, S., and Kuwano, M. (2000) MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment, Clin. Cancer Res., 6, 4618–4627.

    PubMed  CAS  Google Scholar 

  111. Reed, K., Hembruff, S. L., Laberge, M. L., Villeneuve, D. J., Cote, G. B., and Parissenti, A. M. (2008) Hypermethylation of the ABCB1 downstream gene promoter accompanies ABCB1 gene amplification and increased expression in docetaxel–resistant MCF–7 breast tumor cells, Epigenetics, 3, 270–280.

    Article  PubMed  Google Scholar 

  112. El–Osta, A., Kantharidis, P., Zalcberg, J. R., and Wolffe, A. P. (2002) Precipitous release of methyl–CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation, Mol. Cell. Biol., 22, 1844–1857.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Henrique, R., Oliveira, A. I., Costa, V. L., Baptista, T., Martins, A. T., Morais, A., Oliveira, J., and Jeronimo, C. (2013) Epigenetic regulation of MDR1 gene through post–translational histone modifications in prostate cancer, BMC Genomics, 14, 898.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Huo, H., Magro, P. G., Pietsch, E. C., Patel, B. B., and Scotto, K. W. (2010) Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance, Cancer Res., 70, 8726–8735.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Baker, E. K., Johnstone, R. W., Zalcberg, J. R., and El–Osta, A. (2005) Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs, Oncogene, 24, 8061–8075.

    Article  PubMed  CAS  Google Scholar 

  116. Jin, S., and Scotto, K. W. (1998) Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF–Y, Mol. Cell. Biol., 18, 4377–4384.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. El–Khoury, V., Breuzard, G., Fourre, N., and Dufer, J. (2007) The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription–dependent mechanism in a drug–resistant small cell lung carcinoma cell line model, Br. J. Cancer, 97, 562–573.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Balaguer, T. M., Gomez–Martinez, A., Garcia–Morales, P., Lacueva, J., Calpena, R., Reverte, L. R., Riquelme, N. L., Martinez–Lacaci, I., Ferragut, J. A., and Saceda, M. (2012) Dual regulation of P–glycoprotein expression by trichostatin A in cancer cell lines, BMC Mol. Biol., 13, 25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Blandino, G., Fazi, F., Donzelli, S., Kedmi, M., Sas–Chen, A., Muti, P., Strano, S., and Yarden, Y. (2014) Tumor suppressor microRNAs: a novel non–coding alliance against cancer, FEBS Lett., 588, 2639–2652.

    Article  PubMed  CAS  Google Scholar 

  120. Garofalo, M., and Croce, C. M. (2013) MicroRNAs as therapeutic targets in chemoresistance, Drug Resist. Updat., 16, 47–59.

    Article  PubMed  CAS  Google Scholar 

  121. Li, W., Zhang, H., Assaraf, Y. G., Zhao, K., Xu, X., Xie, J., Yang, D. H., and Chen, Z. S. (2016) Overcoming ABC transporter–mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies, Drug Resist. Updat., 27, 14–29.

    Article  PubMed  CAS  Google Scholar 

  122. Livney, Y. D., and Assaraf, Y. G. (2013) Rationally designed nanovehicles to overcome cancer chemoresis–tance, Adv. Drug Deliv. Rev., 65, 1716–1730.

    Article  PubMed  CAS  Google Scholar 

  123. Wijdeven, R. H., Pang, B., Assaraf, Y. G., and Neefjes, J. (2016) Old drugs, novel ways out: drug resistance toward cytotoxic chemotherapeutics, Drug Resist. Updat., 28, 65–81.

    Article  PubMed  Google Scholar 

  124. Geretto, M., Pulliero, A., Rosano, C., Zhabayeva, D., Bersimbaev, R., and Izzotti, A. (2017) Resistance to cancer chemotherapeutic drugs is determined by pivotal microRNA regulators, Am. J. Cancer Res., 7, 1350–1371.

    PubMed  PubMed Central  Google Scholar 

  125. Bruhn, O., Drerup, K., Kaehler, M., Haenisch, S., Roder, C., and Cascorbi, I. (2016) Length variants of the ABCB1 3′–UTR and loss of miRNA binding sites: possible conse–quences in regulation and pharmacotherapy resistance, Pharmacogenomics, 17, 327–340.

    Article  PubMed  CAS  Google Scholar 

  126. Ikemura, K., Yamamoto, M., Miyazaki, S., Mizutani, H., Iwamoto, T., and Okuda, M. (2013) MicroRNA–145 post–transcriptionally regulates the expression and function of P glycoprotein in intestinal epithelial cells, Mol. Pharmacol., 83, 399–405.

    Article  PubMed  CAS  Google Scholar 

  127. Li, N., Yang, L., Wang, H., Yi, T., Jia, X., Chen, C., and Xu, P. (2015) MiR–130a and miR–374a function as novel regulators of cisplatin resistance in human ovarian cancer A2780Cells, PLoS One, 10, e0128886.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Bourguignon, L. Y., Spevak, C. C., Wong, G., Xia, W., and Gilad, E. (2009) Hyaluronan–CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA–21, leading to downregulation of the tumor suppressor protein PDCD4, anti–apoptosis, and chemotherapy resistance in breast tumor cells, J. Biol. Chem., 284, 26533–26546.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Wu, D. D., Li, X. S., Meng, X. N., Yan, J., and Zong, Z. H. (2016) MicroRNA–873 mediates multidrug resistance in ovarian cancer cells by targeting ABCB1, Tumour Biol., 37, 10499–10506.

    Article  PubMed  CAS  Google Scholar 

  130. Tian, S., Zhang, M., Chen, X., Liu, Y., and Lou, G. (2016) MicroRNA–595 sensitizes ovarian cancer cells to cisplatin by targeting ABCB1, Oncotarget, 7, 87091–87099.

    PubMed  PubMed Central  Google Scholar 

  131. Zhu, H., Wu, H., Liu, X., Evans, B. R., Medina, D. J., Liu, C. G., and Yang, J. M. (2008) Role of microRNA miR–27a and miR–451 in the regulation of MDR1/P–glycoprotein expression in human cancer cells, Biochem. Pharmacol., 76, 582–588.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Bitarte, N., Bandres, E., Boni, V., Zarate, R., Rodriguez, J., Gonzalez–Huarriz, M., Lopez, I., Javier Sola, J., Alonso, M. M., Fortes, P., and Garcia–Foncillas, J. (2011) MicroRNA–451 is involved in the self–renewal, tumori–genicity, and chemoresistance of colorectal cancer stem cells, Stem Cells, 29, 1661–1671.

    Article  PubMed  CAS  Google Scholar 

  133. Chen, Z., Ma, T., Huang, C., Zhang, L., Lv, X., Xu, T., Hu, T., and Li, J. (2013) MiR–27a modulates the MDR1/P–glycoprotein expression by inhibiting FZD7/beta–catenin pathway in hepatocellular carcinoma cells, Cell. Signal., 25, 2693–2701.

    Article  PubMed  CAS  Google Scholar 

  134. Kovalchuk, O., Filkowski, J., Meservy, J., Ilnytskyy, Y., Tryndyak, V. P., Chekhun, V. F., and Pogribny, I. P. (2008) Involvement of microRNA–451 in resistance of the MCF–7 breast cancer cells to chemotherapeutic drug doxorubicin, Mol. Cancer Ther., 7, 2152–2159.

    Article  PubMed  CAS  Google Scholar 

  135. Zhao, Y., Qi, X., Chen, J., Wei, W., Yu, C., Yan, H., Pu, M., Li, Y., Miao, L., Li, C., and Ren, J. (2017) The miR–/ Sp3/ABCB1 axis attenuates multidrug resistance of hepatocellular carcinoma, Cancer Lett., 408, 102–111.

    Article  PubMed  CAS  Google Scholar 

  136. Shang, Y., Zhang, Z., Liu, Z., Feng, B., Ren, G., Li, K., Zhou, L., Sun, Y., Li, M., Zhou, J., An, Y., Wu, K., Nie, Y., and Fan, D. (2014) miR–508–5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1, Oncogene, 33, 3267–3276.

    Article  PubMed  CAS  Google Scholar 

  137. Takwi, A. A., Wang, Y. M., Wu, J., Michaelis, M., Cinatl, J., and Chen, T. (2014) miR–137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin–resistant neuroblastoma cells, Oncogene, 33, 3717–3729.

    Article  PubMed  CAS  Google Scholar 

  138. Lu, C., Shan, Z., Li, C., and Yang, L. (2017) MiR–129 regulates cisplatin–resistance in human gastric cancer cells by targeting P–gp, Biomed. Pharmacother., 86, 450–456.

    Article  PubMed  CAS  Google Scholar 

  139. Bao, L., Hazari, S., Mehra, S., Kaushal, D., Moroz, K., and Dash, S. (2012) Increased expression of P–glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR–298, Am. J. Pathol., 180, 2490–2503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Wang, H., Zhan, M., Xu, S. W., Chen, W., Long, M. M., Shi, Y. H., Liu, Q., Mohan, M., and Wang, J. (2017) MiR–218–5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer, Cell Death Dis., 8, e2770.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Genovese, I., Ilari, A., Assaraf, Y. G., Fazi, F., and Colotti, G. (2017) Not only P–glycoprotein: amplification of the ABCB1–containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance–related protein, Drug Resist. Updat., 32, 23–46.

    Article  PubMed  Google Scholar 

  142. Yakusheva, E. N., Titov, D. S., and Nikiforov, A. A. (2016) Effect of combined action of vildagliptin and gliquidone on the functional activity and expression of P–glycoprotein in the norm and in experimental alloxan–induced type 2 diabetes, Ros. Med.–Biol. Vest. im. Akad. I. P. Pavlova, 3, 53–66.

    Google Scholar 

  143. Yakusheva, E. N., and Titov, D. S. (2017) Effect of gliq–uidone on P–glycoprotein expression in the norm and in experimental alloxan–induced type 2 diabetes, Nauka Molodykh (Eruditio Juvenium), 5, 208–224.

    Article  Google Scholar 

  144. Yakusheva, E. N., Titov, D. S., and Pravkin, S. K. (2017) Localization, model of functioning, and physiological functions of P–glycoprotein, Usp. Fiziol. Nauk, 48, 70–87.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D. S. Titov.

Additional information

Original Russian Text © E. N. Yakusheva, D. S. Titov, 2018, published in Biokhimiya, 2018, Vol. 83, No. 8, pp. 1148–1172.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yakusheva, E.N., Titov, D.S. Structure and Function of Multidrug Resistance Protein 1. Biochemistry Moscow 83, 907–929 (2018). https://doi.org/10.1134/S0006297918080047

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297918080047

Keywords

Navigation