JBPC  Vol.2 No.4 , November 2011
Glutathione transferase-P1-1 binding with naturally occurring ligands: assessment by docking simulations
ABSTRACT
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.

Cite this paper
nullDas, A. , Chalil, S. , Nigam, P. , Magee, P. , Janneh, O. and Owusu-Apenten, R. (2011) Glutathione transferase-P1-1 binding with naturally occurring ligands: assessment by docking simulations. Journal of Biophysical Chemistry, 2, 401-407. doi: 10.4236/jbpc.2011.24046.
References
[1]   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

[2]   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

[3]   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

[4]   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

[5]   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

[6]   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

[7]   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

[8]   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

[9]   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

[10]   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

[11]   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

[12]   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

[13]   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

[14]   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

[15]   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

[16]   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

[17]   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.

[18]   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

[19]   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

[20]   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

[21]   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

[22]   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

[23]   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

[24]   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.

[25]   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.

[26]   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

[27]   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.

 
 
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