Skip to main content
SpringerLink
Log in

Homology modeling of a novel epoxide hydrolase (EH) from Aspergillus niger SQ-6: structure-activity relationship in expoxides inhibiting EH activity

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

The 3D structure of a novel epoxide hydrolase from Aspergillus niger SQ-6 (sqEH) was constructed by using homology modeling and molecular dynamics simulations. Based on the 3D model, Asp191, His369 and Glu343 were predicted as catalytic triad. The putative active pocket is a hydrophobic environment and is rich in some important non—polar residues (Pro318, Trp282, Pro319, Pro317 and Phe242). Using three sets of epoxide inhibitors for docking study, the interaction energies of sqEH with each inhibitor are consistent with their inhibitory effects in previous experiments. Moreover, a critical water molecule which closes to the His369 was identified to be an ideal position for the hydrolysis step of the reaction. Two tyrosine residues (Tyr249 and Tyr312) are able to form hydrogen bonds with the epoxide oxygen atom to maintain the initial binding and positioning of the substrate in the active pocket. These docked complex models can well interpret the substrate specificity of sqEH, which could be relevant for the structural—based design of specific epoxide inhibitors.

 

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Arand M, Oesch F (2002) Wiley, New York, pp 459-483

  2. Armstrong RN (1999) Drug Metab Rev 31:71–86

    Article  CAS  Google Scholar 

  3. Oesch F (1973) Xenobiotica 3:305–340

    Article  CAS  Google Scholar 

  4. Arand M, Wagner H, Oesch F (1996) J Biol Chem 271:4223–4229

    Article  CAS  Google Scholar 

  5. Lacourciere GM, Armstrong RN (1993) J Am Chem Soc 115:10466–10467

    Article  CAS  Google Scholar 

  6. Weijers CAGM, de Bont JAM (1999) J Mol Catal B Enzym 6:199–214

    Article  CAS  Google Scholar 

  7. Armstrong RN, Cassidy CS (2000) Drug Metab Rev 32:327–338

    Article  CAS  Google Scholar 

  8. Rink R, Fennema F, Smids M, Dehmel U, Janssen DB (1997) J Biol Chem 272:14650–14657

    Article  CAS  Google Scholar 

  9. Arand M, Hemmer H, DSrk H, Baratti J, Archelas A, Furstoss R, Oesch F (1999) Biochem J 344:273–280

    Article  CAS  Google Scholar 

  10. Wojtasek H, Prestwich GD (1996) Biochem Biophys Res Commun 220:323–329

    Article  CAS  Google Scholar 

  11. Ready JM, Jacobsen EN (2001) J Am Chem Soc 123:2687–2688

    Article  CAS  Google Scholar 

  12. Bell PA, Kasper CB (1993) J Biol Chem 268:14011–14017

    CAS  Google Scholar 

  13. Laughlin LT, Tzeng HF, Lin S, Armstrong RN (1998) Biochemistry 37:2897–2904

    Article  CAS  Google Scholar 

  14. Moussou P, Archelas A, Furstoss R (1998) J Mol Catal B Enzym 5:447–458

    Article  CAS  Google Scholar 

  15. Moussou P, Archelas A, Baratti J, Furstoss R (1998) Tetrahedron: Asymmetry 9:1539–1547

    Article  CAS  Google Scholar 

  16. Cleij M, Archelas A, Furstoss R (1998) Tetrahedron: Asymmetry 9:1839–1842

    Article  CAS  Google Scholar 

  17. Liu Y, Wu S, Wang J, Yang L, Sun W (2007) Protein Expr Purif 53:239–246

    Article  CAS  Google Scholar 

  18. Zou J, Hallberg BM, Bergfors T, Oesch F, Arand M, Mowbray SL, Jones TA Structure 8:111–122

  19. Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Nucleic Acids Res 25:3389–3402

    Article  CAS  Google Scholar 

  20. Higgins DG, Bleasby AJ, Fuchs R (1992) Comput Appl Biosci 8:189–191

    CAS  Google Scholar 

  21. Ke YY, Chen YC, Lin TH (2006) J Comput Chem 27:1556–1570

    Article  CAS  Google Scholar 

  22. Gui C, Zhu W, Chen G, Luo X, Liew OW, Puah CM, Chen K, Jiang H (2007) Proteins 67:41–52

    Article  CAS  Google Scholar 

  23. Accelrys. InsightII, Version 2000, Homology User Guide. San Diego: Biosym/MSI

  24. Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Pearlman DA, Crowley M, Walker RC, Zhang W, Wang B, Hayik S, Roitberg A, Seabra G, Wong KF, Paesani F, Wu X, Brozell S, Tsui V, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Beroza P, Mathews DH, Schafmeister C, Ross WS, Kollman PA (2006) AMBER 9 University of California San Francisco

  25. Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods R (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688

    Article  CAS  Google Scholar 

  26. Ponder JW, Case DA (2003) Adv Prot Chem 66:27–85

    Article  CAS  Google Scholar 

  27. Simmerling C, Strockbine B, Roitberg AE (2002) J Am Chem Soc 124:11258–11259

    Article  CAS  Google Scholar 

  28. Pastor RW, Brooks BR, Szabo A (1988) Mol Phys 65:1409–1419

    Article  Google Scholar 

  29. Tuccinardi T, Manetti F, Schenone S, Martinelli A, Botta M (2007) J Chem Inf Model 47:644–655

    Article  CAS  Google Scholar 

  30. Accelrys. InsightII, Version 2000, Profiles-3D. San Diego: Biosym/MSI

  31. Lüthy R, Bowie JU, Eisenberg D (1992) Nature 356:83–85

    Article  Google Scholar 

  32. Laskowski RA, Macarthur MW, Moss DS, Thornton JM (1993) J Appl Crystallogr 26:283–291

    Article  CAS  Google Scholar 

  33. Binding site analysis user guide. (2000) San Diego, USA: Accelrys, Inc

  34. Affinity San Diego Molecular Simulations Inc (2000)

  35. Bartlett PA, Shea GT, Telfer SJ, Waterman S (1989) R Soc Chem 182–196

  36. Shoichet BK, Kuntz ID, Bodian DL (1992) J Comput Chem 13:380–397

    Article  CAS  Google Scholar 

  37. Nardini M, Dijkstra BW (1999) Curr Opin Struct Biol 9:732–737

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Science Foundation of China (20333050, 20673044), PCSIRT (IRT0625), Key subject of Science and Technology by Jilin Province and 985 Graduate Innovation Program of Jilin University (20080220). We also thank professor David A. Case et al for providing us the Amber 9 software as a freeware.

Author information

Authors and Affiliations

  1. State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, 130023, People’s Republic of China

    Quan Luo, Yuan Yao, Wei-Wei Han, Yi-Han Zhou & Ze-Sheng Li

Authors
  1. Quan Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei-Wei Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-Han Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ze-Sheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ze-Sheng Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, Q., Yao, Y., Han, WW. et al. Homology modeling of a novel epoxide hydrolase (EH) from Aspergillus niger SQ-6: structure-activity relationship in expoxides inhibiting EH activity. J Mol Model 15, 1125–1132 (2009). https://doi.org/10.1007/s00894-009-0466-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-009-0466-5

Keywords

Search

Navigation