Glutathione transferase-P1-1 (hGSTP1-1), which is associated with acquired drug resistance in some tumour cells, requires two identical subunits for full activity. Naturally occurring inhibitors for GSTP1-1 quaternary structure could be interesting therapeutic agents. The aim of this study was to investigate potential binding sites for hGSTP1-1 interaction with ligands many of which occur naturally. Simulations were performed with commercial docking software and with GST monomer or dimer as template. Docking results using hGSTP1-1 dimer showed one binding site for most of the ligands tested. Lycopene, glutathione, ellagic acid, ethacrynic acid, quercetin, caffeic acid, ferulic acid, porphyrin, curcumin, cinnamic acid, and also α-tocopherol bound at the enzyme dimer subunit-subunit interface. In contrast, investigations using hGSTP1-1 monomer revealed three additional sites for ligand binding. In conclusion, the docking simulations suggest that the enzyme subunit interface may be important for hGSTP1-1 interactions with ligands. These findings may provide valuable insights for further research to identify naturally occurring therapeutic agents.
Townsend, D.M. and Tew, K.D. (2003) The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene, 22, 7369-7365. doi:10.1038/sj.onc.1206940
Tew, K.D. and Townsend D.M. (2011) Regulatory functions of glutathione S-transferase P1-1 unrelated to detoxification. Drug Metabolism Reviews, 43, 179-193. doi:10.3109/03602532.2011.552912
Reinemer, P., Dirr, H.W., Ladenstein, R., Sch?ffer, J., Gallay, O. and Huber, R. (1991) The three-dimensional structure of class π glutathione S-transferase in complex with glutathione sulfonate at 2.3 ? resolution. EMBO Journal, 10, 1997-2005. doi:10.1016/0022-2836(92)90692-D
Dirr, H., Reinemer P. and Huber R. (1994) Refined crystal structure of porcine Pi glutathione S-transferase (pG ST P1-1) at 2.1 ? resolution. Journal of Molecular Biology, 234, 72-92. doi:10.1006/jmbi.1994.1631
Balchin, D., Fanucchi, S., Achilonu, I., Adamson R.J., Burke, J., Fernandes, M., Gildenhuys, S. and Dirr, H.W. (2010) Stability of the domain interface contributes towards the catalytic function at the H-site of class alpha glutathione transferase A1-1. Biochimica et Biophysica Acta-Proteins and Proteomics, 1804, 2228-2233. doi:10.1016/j.bbapap.2010.09.003
Fabrini, R., De Luca, A., Stella, L., Mei, G., Orioni, B., Ciccone, S., Federici, G., Bello, M.L. and Ricci, G. (2009) Monomer-dimer equilibrium in glutathione transferases: A critical re-examination. Biochemistry, 48, 10473-10482. doi:10.1021/bi901238t
Oakley, A.J., Rossjohn, J., Lo Bello, M., Caccuri, A.M., Federici, G. and Parker, M.W. (1997) The three-dimen- sional structure of the human P1-1 class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate. Biochemistry, 36, 576- 585. doi:10.1021/bi962316i
Oakley, A.J., Bello, M.L., Nuccetelli, M., Mazzetti, A.P. and Parker, M.W. (1999) The ligandin (non-substrate) binding site of human P1-1 class glutathione transferase is located in the electrophile binding site (H-site). Journal of Molecular Biology, 291, 913-926. doi:10.1006/jmbi.1999.3029
Ralat, L.A. and Colman, R.F. (2004) Glutathione S- transferase Pi has at least three distinguishable xenobiotic substrate sites close to its glutathione-binding site. Journal of Biological Chemistry, 279, 50204-50213. doi:10.1074/jbc.M407445200
Van Haaten, R.I.M., Evelo, C.T.A., Penders, J., Eijnwachter, M.P., Haenen, G.R. and Bast, A. (2001) Inhibition of human glutathione S-transferase P1-1 by tocopherols and α-tocopherol derivatives. Biochimica Biophysical Ac- ta―Protein Structure and Molecular Enzymology, 1548, 23-28. doi:10.1016/S0167-4838(01)00211-4
van Haaften, R.I.M., Evelo, C.T.A, Haenen, G.R.M.M. and Bast, A. (2001) α-Tocopherol inhibits human glutathione S-transferase p. Biochemical and Biophysical Research Communications, 280, 631-633. doi:10.1006/bbrc.2000.4174
van Zanden, J.J., Ben Hamman, O., van Lersel, M.L.PS., Boeren, S., Cnubben, N.H.P., Bellod, M.L., Vervoort J., van Bladerena, P.J. and Rietjensa, I.M.C.M. (2003) Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin. Chemico-Biological Interactions, 145, 39-148. doi:10.1016/S0009-2797(02)00250-8
Hayeshi, R., Mutingwende, I., Mavengere, W., Masiyanise, V. and Mukanganyama, S. (2007) The inhibition of human glutathione S-transferases activity by plant polyphenolic compounds ellagic acid and curcumin. Food and Chemical Toxicology, 45, 286-295. doi:10.1016/j.fct.2006.07.027
Nathan, S.T., Mathew, N., Kalyanasundaram, M. and Balaraman, K. (2005) Structure of glutathione S-trans- ferase of the filarial parasite Wuchereria bancrofti: A tar- get for drug development against adult worm. Journal of Molecular Modelling, 11, 194-199. doi:10.1007/s00894-005-0234-0
Yadav, M., Singh, A., Rathaur, S. and Liebau E. (2010) Structural modelling and simulation studies of Brugia malayi glutathione-S-transferase with compounds exhibiting antifilarial activity: Implications in drug targeting and designing. Journal of Molecular Graphics and Modelling, 28, 435-445. doi:10.1016/j.jmgm.2009.10.003
Srinivasan, L., Mathew, N. and Muthuswamy, K. (2010) In-Vitro antifilarial activity of glutathione S-transferase inhibitors. Parasitology Research, 105, 1179-1182. doi: 10.1007/s00436-009-1534-6
Kapoli, P., Axarli, I.A., Platis, D., Fragoulaki, M., Paine, M., Hemingway, J., Vontas, J. and Labrou, N.E. (2008) Engineering sensitive glutathione transferase for the detection of xenobiotics. Biosensors and Bioelectronics, 24, 498-503.
Setzer, W. N. (2010) The molecular mechanism for DDT detoxification in Anopheles gambiae: A molecular docking study. Journal of Biophysical Chemistry, 2, 135-136. doi.10.4236/jbpc.2011.22016
Quesada-Soriano, I., Parker, L.J., Primavera, A., Casas- Solvas, J.M., Vargas-Berenguel, A., Barón, C., Morton, C.J., Mazzetti, A.P., Lo Bello, M., Parker, M.W. and García-Fuentes, L. (2009) Influence of the H-site residue 108 on human glutathione transferase P1-1 ligand binding: Structure-thermodynamic relationships and thermal stability. Protein Science, 18, 2454-2470. doi:10.1002/pro.253
Adler, V., Yin, Z.M., Fuchs, S.Y., Benezra, M., Rosario, L., Tew, K.D., Pincus, M.R., Sardana, M., Henderson, C.J., Wolf, C.R., Davis, R.J. and Ronai, Z. (1999) Regulation of JNK signalling by GSTp. EMBO Journal, 18, 1321-1334. doi:10.1093/emboj/18.5.1321
Gildenhuys, S., Wallace, L.A., Burke, J.P., Balchin, D., Sayed, Y. and Dirr H.W. (2010) Class Pi glutathione transferase unfolds via a dimeric and not monomeric intermediate: Functional implications for an unstable monomer. Biochemistry, 49, 5074-5081. doi:10.1021/bi100552d
Stenberg, G., Abdalla, A.M. and Mannervik, B. (2000) Tyrosine 50 at the subunit interface of dimeric human glutathione transferase P1-1 is a structural key residue for modulating protein stability and catalytic function. Biochemical and Biophysical Research Communications, 27, 59-63. doi:10.1006/bbrc.2000.2579
Wongsantichon, J. and Ketterman, A. J. (2006) An intersubunit lock-and-key ‘Clasp’ motif in the dimer interface of Delta class glutathione transferase. Biochemical Journal, 394, 135-144. doi:10.1042/BJ20050915
Artali, R., Beretta, G., Morazzoni, P., Bombardelli, E. and Meneghetti, F. (2009) Green tea catechins in chemoprevention of cancer: A molecular docking investigation into their interaction with glutathione-S-transferase (GST- P1-1). Journal of Enzyme Inhibition and Medicinal Chemistry, 24, 287-295.
Leach, A.R., Shoichet, B.K. and Peishoff, C.E. (2006) Predictions of protein-ligand interactions. Docking and scoring: Successes and gaps. Journal of Medicinal Che- mistry, 49, 5851-5855.
Leal, M., Shimada, A., Ruiz, F. and González de Mejía, E. (1999) Effect of lycopene on lipid peroxidation and glutathione-dependent enzymes induced by T-2 toxin in vivo. Toxicology Letters, 109, 1-10. doi:10.1016/S0378-4274(99)00062-4
Bhosale, P., Larson, A.J., Frederick, J.M., Southwick, K., Thulin, C.D. and Bernstein, P.S. (2004) Identification and characterization of a Pi isoform of glutathione S-trans- ferase (GSTP1) as a zeaxanthin-binding protein in the macula of the human eye. Journal of Biological Chemistry, 279, 49447-49454.