Molecular modeling studies of ABC transporters involved in multidrug resistance

Mini-Reviews in Medicinal Chemistry

Volumn 9, Issue 2, 2009, Pages 186-193

  Ravna, Aina Westrheim ^a   Sager, Georg ^a  

^a UNIVERSITY OF TROMSØ   (Norway)

Author keywords

Molecular modeling; MRP4 ABCC4; MRP5 ABCC5; Multidrug resistance; P glycoprotein ABCB1

Indexed keywords

ABC TRANSPORTER; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ANTIBIOTIC AGENT; ANTINEOPLASTIC AGENT; CENTRAL NERVOUS SYSTEM AGENTS; CYTOTOXIC AGENT; DAUNORUBICIN; DOXORUBICIN; ELACRIDAR; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 1 INHIBITOR; MULTIDRUG RESISTANCE PROTEIN 4; MULTIDRUG RESISTANCE PROTEIN 5; ONTOGEN; PROTEIN INHIBITOR; TARIQUIDAR; TOPOTECAN; UNCLASSIFIED DRUG; VERAPAMIL; VINCRISTINE; ZOSUQUIDAR;

ANTIBIOTIC THERAPY; ARTICLE; CANCER CHEMOTHERAPY; CLINICAL TRIAL; DRUG EFFICACY; DRUG STRUCTURE; DRUG TARGETING; HUMAN; HUMAN GENOME; IN VITRO STUDY; IN VIVO STUDY; MALIGNANT NEOPLASTIC DISEASE; MOLECULAR MODEL; MULTIDRUG RESISTANCE; PHYLOGENY; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN STRUCTURE; PROTEIN TRANSPORT; QUANTITATIVE STRUCTURE ACTIVITY RELATION; SITE DIRECTED MUTAGENESIS; UNSPECIFIED SIDE EFFECT; X RAY CRYSTALLOGRAPHY; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; GENETICS; METABOLISM; MOLECULAR GENETICS; NUCLEOTIDE SEQUENCE; REVIEW;

ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; BASE SEQUENCE; DRUG RESISTANCE, MULTIPLE; HUMANS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA;

EID: 65449164244     PISSN: 13895575     EISSN: None     Source Type: Journal    
DOI: 10.2174/138955709787316065     Document Type: Article

References (70)

1. Dantzig, A.H.; de Alwis, D.P.; Burgess, M. Considerations in the design and development of transport inhibitors as adjuncts to drug therapy. Adv. Drug Deliv. Rev., 2003, 55, 133-50.
2. Saier, M.H., Jr. A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol. Mol. Biol. Rev., 2000, 64, 354-411.
3. Dassa, E.; Bouige, P. The ABC of ABCS: a phylogenetic and functional classification of ABC systems in living organisms. Res. Microbiol., 2001, 152, 211-29.
4. Dean, M.; Rzhetsky, A.; Allikmets, R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res., 2001 11, 1156-66.
5. Walker, J.E.; Saraste, M.; Runswick, M.J.; Gay, N.J. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J., 1982, 1, 945-51.
6. Oswald, C.; Holland, I.B.; L., S. The motor domains of ABC-transporters - What can structures tell us? Naunyn-Schmiedeberg's Arch. Pharmacol., 2006, 372, 385-99.
7. Ejendal, K.F.; Hrycyna, C.A. Multidrug resistance and cancer: the role of the human ABC transporter ABCG2. Curr. Protein Pept. Sci., 2002, 3, 503-11.
8. Leslie, E.M.; Deeley, R.G.; Cole, S.P. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol., 2005, 204, 216-37.
9. Ross, D.D.; Doyle, L.A. Mining our ABCs: pharmacogenomic approach for evaluating transporter function in cancer drug resistance. Cancer Cell, 2004, 6, 105-7.
10. Sampath, J.; Adachi, M.; Hatse, S.; Naesens, L.; Balzarini, J.; Flatley, R.M.; Matherly, L.H.; Schuetz, J.D. Role of MRP4 and MRP5 in biology and chemotherapy. AAPS PharmSci., 2002, 4, E14.
11. Cordon-Cardo, C.; O'Brien, J.P.; Casals, D.; Rittman-Grauer, L.; Biedler, J.L.; Melamed, M.R.; Bertino, J.R. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at bloodbrain barrier sites. Proc. Natl. Acad. Sci. U S A, 1989, 86, 695-8.
12. McDevitt, C.A.; Callaghan, R. How can we best use structural information on P-glycoprotein to design inhibitors? Pharmacol. Ther., 2007, 113, 429-41.
13. Borst, P.; de Wolf, C.; van de Wetering, K. Multidrug resistance associated proteins 3, 4, and 5. Pflugers Arch., 2007, 453, 661-73.
14. Leggas, M.; Adachi, M.; Scheffer, G.L.; Sun, D.; Wielinga, P.; Du, G.; Mercer, K.E.; Zhuang, Y.; Panetta, J.C.; Johnston, B.; Scheper, R.J.; Stewart, C.F.; Schuetz, J.D. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol. Cell Biol., 2004, 24, 7612-21.
15. Rius, M.; Hummel-Eisenbeiss, J.; Hofmann, A.F.; Keppler, D. Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione. Am. J. Physiol. Gastrointest. Liver Physiol., 2006, 290, G640-9.
16. Rius, M.; Thon, W.F.; Keppler, D.; Nies, A.T. Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract. J. Urol., 2005, 174, 2409-14.
17. Van Aubel, R.A.; Smeets, P.H.; van den Heuvel, J.J.; Russel, F.G. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am. J. Physiol. Renal Physiol., 2005, 288, F327-33.
18. Nies, A.T.; Jedlitschky, G.; Konig, J.; Herold-Mende, C.; Steiner, H.H.; Schmitt, H.P.; Keppler, D. Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1- ABCC6), in human brain. Neuroscience, 2004, 129, 349-60.
19. van Aubel, R.A.; Smeets, P.H.; Peters, J.G.; Bindels, R.J.; Russel, F.G. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J. Am. Soc. Nephrol., 2002, 13, 595-603.
20. Rius, M.; Nies, A.T.; Hummel-Eisenbeiss, J.; Jedlitschky, G.; Keppler, D. Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology, 2003, 38, 374-84.
21. Klokouzas, A.; Wu, C.P.; van Veen, H.W.; Barrand, M.A.; Hladky, S.B. cGMP and glutathione-conjugate transport in human erythrocytes. Eur. J. Biochem., 2003, 270, 3696-708.
22. Jedlitschky, G.; Tirschmann, K.; Lubenow, L.E.; Nieuwenhuis, H.K.; Akkerman, J.W.; Greinacher, A.; Kroemer, H.K. The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage. Blood, 2004, 104, 3603-10.
23. Zelcer, N.; Reid, G.; Wielinga, P.; Kuil, A.; van der Heijden, I.; Schuetz, J.D.; Borst, P. Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATPbinding cassette C4). Biochem. J., 2003, 371, 361-7.
24. Konig, J.; Hartel, M.; Nies, A.T.; Martignoni, M.E.; Guo, J.; Buchler, M.W.; Friess, H.; Keppler, D. Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int. J. Cancer, 2005, 115, 359-67.
25. Jedlitschky, G.; Burchell, B.; Keppler, D. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J. Biol. Chem., 2000, 275, 30069-74.
26. Dazert, P.; Meissner, K.; Vogelgesang, S.; Heydrich, B.; Eckel, L.; Bohm, M.; Warzok, R.; Kerb, R.; Brinkmann, U.; Schaeffeler, E.; Schwab, M.; Cascorbi, I.; Jedlitschky, G.; Kroemer, H.K. Expression and localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart. Am. J. Pathol., 2003, 163, 1567-77.
27. Meyer Zu Schwabedissen, H.E.; Grube, M.; Heydrich, B.; Linnemann, K.; Fusch, C.; Kroemer, H.K.; Jedlitschky, G. Expression, localization, and function of MRP5 (ABCC5), a transporter for cyclic nucleotides, in human placenta and cultured human trophoblasts: effects of gestational age and cellular differentiation. Am. J. Pathol., 2005, 166, 39-48.
28. Belinsky, M.G.; Bain, L.J.; Balsara, B.B.; Testa, J.R.; Kruh, G.D. Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins. J. Natl. Cancer Inst., 1998, 90, 1735-41.
29. Kool, M.; de Haas, M.; Scheffer, G.L.; Scheper, R.J.; van Eijk, M.J.; Juijn, J.A.; Baas, F.; Borst, P. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res., 1997, 57, 3537-47.
30. McAleer, M.A.; Breen, M.A.; White, N.L.; Matthews, N. pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J. Biol. Chem., 1999, 274, 23541-8.
31. Nies, A.T.; Spring, H.; Thon, W.F.; Keppler, D.; Jedlitschky, G. Immunolocalization of multidrug resistance protein 5 in the human genitourinary system. J. Urol., 2002, 167, 2271-5.
32. Wieman, H.; Tondel, K.; Anderssen, E.; Drablos, F. Homologybased modelling of targets for rational drug design. Mini. Rev. Med. Chem., 2004, 4, 793-804.
33. Born, M.; Oppenheimer, R. Zur Quantentheorie der Molekeln. Annalen der Physik, 1927, 84, 457-84.
34. Burkert, U.; Allinger, N.L., Molecular Mechanics. American Chemical Society. Washington, DC Vol. 177, 1982.
35. Alder, B.J.; Wainwright, T.E. Studies in Molecular Dynamics. I. General Method. J. Chem. Physics, 1959, 31, 459-66.
36. Abagyan, R.; Totrov, M. Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. J. Mol. Biol., 1994, 235, 983-1002.
37. Metropolis, N.; Ulam, S. The Monte Carlo Method. J. Am. Stat. Assoc., 1949, 44, 335-41.
38. Chalmers, A.F., What is this thing called science? Buckingham: Open University Press 2002.
39. Dawson, R.J.; Locher, K.P. Structure of a bacterial multidrug ABC transporter. Nature, 2006.
40. Ravna, A.W.; Sager, G. Molecular model of the outward facing state of the human multidrug resistance protein 4 (MRP4/ABCC4). Bioorg. Med. Chem. Lett., 2008, 18, 3481-3.
41. Ravna, A.W.; Sylte, I.; Sager, G. Molecular model of the outward facing state of the human P-glycoprotein (ABCB1), and comparison to a model of the human MRP5 (ABCC5). Theor. Biol. Med. Model., 2007, 4, 33.
42. Hibert, M.F.; Trumpp-Kallmeyer, S.; Bruinvels, A.; Hoflack, J. Three-dimensional models of neurotransmitter G-binding proteincoupled receptors. Mol. Pharmacol., 1991, 40, 8-15.
43. Igarashi, Y.; Aoki, K.F.; Mamitsuka, H.; Kuma, K.; Kanehisa, M. The evolutionary repertoires of the eukaryotic-type ABC transporters in terms of the phylogeny of ATP-binding domains in eukaryotes and prokaryotes. Mol. Biol. Evol., 2004, 21, 2149-60.
44. Zolnerciks, J.K.; Wooding, C.; Linton, K.J. Evidence for a Sav1866-like architecture for the human multidrug transporter Pglycoprotein. FASEB J., 2007, 21, 3937-48.
45. Borst, P.; Evers, R.; Kool, M.; Wijnholds, J. The multidrug resistance protein family. Biochim. Biophys. Acta, 1999, 1461, 347-57.
46. McDevitt, C.A.; Shintre, C.A.; Gunter Grossmann, J.; Pollock, N.L.; Prince, S.M.; Callaghan, R.; Ford, R.C. Structural insights into P-glycoprotein (ABCB1) by small angle X-ray scattering and electron crystallography. FEBS Lett., 2008, 582, 2950-6.
47. Ward, A.; Reyes, C.L.; Yu, J.; Roth, C.B.; Chang, G. Flexibility in the ABC transporter MsbA: Alternating access with a twist. Proc. Natl. Acad. Sci. USA, 2007, 104, 19005-10.
48. Chang, G.; Roth, C.B. Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science, 2001, 293, 1793-800.
49. Chang, G. Structure of MsbA from Vibrio cholera: a multidrug resistance ABC transporter homolog in a closed conformation. J. Mol. Biol., 2003, 330, 419-30.
50. Reyes, C.L.; Chang, G. Structure of the ABC transporter MsbA in complex with ADP.vanadate and lipopolysaccharide. Science, 2005, 308, 1028-31.
51. Chang, G.; Roth, C.B.; Reyes, C.L.; Pornillos, O.; Chen, Y.J.; Chen, A.P. Retraction. Science, 2006, 314, 1875.
52. Ravna, A.W.; Sylte, I.; Sager, G. A molecular model of a putative substrate releasing conformation of multidrug resistance protein 5 (MRP5). Eur. J. Med. Chem., 2008, 43, 2557-67.
53. Muller, M.; Mayer, R.; Hero, U.; Keppler, D. ATP-dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P-glycoprotein. FEBS Lett., 1994, 343, 168-72.
54. Orlowski, S.; Garrigos, M. Multiple recognition of various amphiphilic molecules by the multidrug resistance P-glycoprotein: molecular mechanisms and pharmacological consequences coming from functional interactions between various drugs. Anticancer Res., 1999, 19, 3109-23.
55. Smit, J.W.; Duin, E.; Steen, H.; Oosting, R.; Roggeveld, J.; Meijer, D.K. Interactions between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level. Br. J. Pharmacol., 1998, 123, 361-70.
56. Wang, E.J.; Lew, K.; Casciano, C.N.; Clement, R.P.; Johnson, W.W. Interaction of common azole antifungals with P glycoprotein. Antimicrob. Agents Chemother., 2002, 46, 160-5.
57. Sager, G. Cyclic GMP transporters. Neurochem. Int., 2004, 45, 865-73.
58. Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Transmembrane segment 1 of human P-glycoprotein contributes to the drug-binding pocket. Biochem. J., 2006, 396, 537-45.
59. Loo, T.W.; Clarke, D.M. Location of the rhodamine-binding site in the human multidrug resistance P-glycoprotein. J. Biol. Chem., 2002, 277, 44332-8.
60. Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Methanethiosulfonate derivatives of rhodamine and verapamil activate human Pglycoprotein at different sites. J. Biol. Chem., 2003, 278, 50136-41.
61. Loo, T.W.; Clarke, D.M. Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux. J. Membr. Biol., 2005, 206, 173-85.
62. Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Disulfide cross-linking analysis shows that transmembrane segments 5 and 8 of human Pglycoprotein are close together on the cytoplasmic side of the membrane. J. Biol. Chem., 2004, 279, 7692-7.
63. Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Val133 and Cys137 in transmembrane segment 2 are close to Arg935 and Gly939 in transmembrane segment 11 of human P-glycoprotein. J. Biol. Chem., 2004, 279, 18232-8.
64. Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Substrate-induced conformational changes in the transmembrane segments of human Pglycoprotein. Direct evidence for the substrate-induced fit mechanism for drug binding. J. Biol. Chem., 2003, 278, 13603-6.
65. Peters, K.M.; Schuman, J.T.; Skurray, R.A.; Brown, M.H.; Brennan, R.G.; Schumacher, M.A. QacR-cation recognition is mediated by a redundancy of residues capable of charge neutralization. Biochemistry, 2008, 47, 8122-9.
66. Thomas, H.; Coley, H.M. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control., 2003, 10, 159-65.
67. Hyafil, F.; Vergely, C.; Du Vignaud, P.; Grand-Perret, T. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res., 1993, 53, 4595-602.
68. Slate, D.L.; Bruno, N.A.; Casey, S.M.; Zutshi, N.; Garvin, L.J.; Wu, H.; Pfister, J.R. RS-33295-198: a novel, potent modulator of P-glycoprotein-mediated multidrug resistance. Anticancer Res., 1995, 15, 811-4.
69. Roe, M.; Folkes, A.; Ashworth, P.; Brumwell, J.; Chima, L.; Hunjan, S.; Pretswell, I.; Dangerfield, W.; Ryder, H.; Charlton, P. Reversal of P-glycoprotein mediated multidrug resistance by novel anthranilamide derivatives. Bioorg. Med. Chem. Lett., 1999, 9, 595-600.
70. Newman, M.J.; Rodarte, J.C.; Benbatoul, K.D.; Romano, S.J.; Zhang, C.; Krane, S.; Moran, E.J.; Uyeda, R.T.; Dixon, R.; Guns, E.S.; Mayer, L.D. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Res., 2000, 60, 2964-72. Received: 22 August, 2008 Revised: 30 October, 2008 Accepted: 07 November, 2008