Theoretical Investigations on Structure and Function of Human Homologue hABH4 of E.coli ALKB4

  • Received : 2010.08.27
  • Accepted : 2010.09.07
  • Published : 2010.09.30


Introduction: Recently identified human homologues of ALKB protein have shown the activity of DNA damaging drugs, used for cancer therapy. Bioinformatics study of hABH2 and hABH3 had led to the discovery of a novel DNA repair mechanism. Very little is known about structure and function of hABH4, one of the members of this superfamily. Therefore, in present study we are intended to predict its structure and function through various bioinformatics tools. Materials and Methods: Modeling was done with modeler 9v7 to predict the 3D structure of the hABH4 protein. This model was validated with the program Procheck using Ramachandran plot statistics and was submitted to PMDB with ID PM0076284. The 3d2GO server was used to predict the functions. Residues at protein ligand and protein RNA binding sites were predicted with 3dLigandSite and KYG programs respectively. Results and Discussion: 3-D model of hABH4, ALKBH4.B99990003.pdb was predicted and evaluated. Validation result showed that 96.4 % residues lies in favored and additional allowed region of Ramachandran plot. Ligand binding residues prediction showed four Ligand clusters, having 24 ligands in cluster 1. Importantly, conserved pattern of Glu196-X-Pro198- Xn-His254 in the functional domain was detected. DNA and RNA binding sites were also predicted in the model. Conclusion and Prospects: The predicted and validated model of human homologue hABH4 resulted from this study may unveil the mechanism of DNA damage repair in human and accelerate the research on designing of appropriate inhibitors aiding in chemotherapy and cancer related diseases.


  1. Mishina, Y., Duguid, E.M., and He, C. (2006). Direct reversal of DNA alkylation damage. Chem Rev 106, 215-232.
  2. Kurowski, M.A., Bhagwat, A.S., Papaj, G., and Bujnicki, J.M. (2003). Phylogenomic identification of five new human homologs of the DNA repair enzyme AlkB. BMC Genomics 4, 48.
  3. van den Born, E., Bekkelund, A., Moen, M.N., Omelchenko, M.V., Klungland, A., and Falnes, P.O. (2009). Bioinformatics and functional analysis define four distinct groups of AlkB DNA-dioxygenases in bacteria. Nucleic Acids Res 37, 7124-7136.
  4. Helleday, T., Petermann, E., Lundin, C., Hodgson, B., and Sharma, R.A. (2008). DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8, 193-204.
  5. Bjornstad, L. (2007). Characterization of the human AlkB homologueue 4 (hABH4). Characterization-human-AlkB-homologueue-4/0030112494.html.
  6. Jones, D.T. (1999). GenTHREADER: an efficient and reliableprotein fold recognition method for genomic sequences. J Mol Biol 287, 797-815.
  7. Laskoswki, R.A., MacArthur, M. W., Moss, D. S. and Thorton, J. M. (1993). PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Cryst. 26, 283-291.
  8. Shankaracharya, Srivastava, B., Vidyarthi, A. S. (2010). Structure modeling of VRK1 Protein and Its Molecular Docking study with Ribavirin analogs. Int. J. Pharm. and Bio Sci. 1(3), 1-10.
  9. Shankaracharya, Sharma, P., Vidyarthi, A. S. (2010). Homology Modeling of Tubulin ${\beta}$-1 chain and its Docking study with Colchicine Analogs. Int. J. Pharmacy and Technology. 3(2), 513-527.
  10. Shankaracharya, Priyamvada, Vidyarthi, A. S. (2010). Pharmaco-inforamtics: Modeling of Human CDCP2 homologue structure and its docking study with Flavopiridol analogs. Int. J. Pharm. Sci. Rev. Res. 4, 1-6.
  11. Shankaracharya, Priyamvada, Vidyarthi, A. S. (2010). Structural Modeling of Human CDK4 and its Docking study with flavopiridol analogues. PHARMBIT, Jan-Jun. (Accepted)
  12. Westbye, M.P., Feyzi, E., Aas, P.A., Vagbo, C.B., Talstad, V.A., Kavli, B., Hagen, L., Sundheim, O., Akbari, M., Liabakk, N.B., et al. (2008). Human AlkB homolog 1 is a mitochondrial protein that demethylates 3-methylcytosine in DNA and RNA. J Biol Chem 283, 25046-25056.
  13. Wass, M.N., and Sternberg, M.J. (2009). Prediction of ligand binding sites using homologous structures and conservation at CASP8. Proteins 77(9), 147-151.
  14. Terribilini, M., Lee, J.H., Yan, C., Jernigan, R.L., Honavar, V., and Dobbs, D. (2006). Prediction of RNA binding sites in proteins from amino acid sequence. RNA 12(8), 1450-1462.
  15. Shankaracharya, Das, S., Vidyarthi, A. S. (2010). Homology Modeling and Function Prediction of hABH1, Involve in repair of alkylation-damaged DNA. Interdisciplinary Sciences. Computational Life Sciences (Accepted).
  16. Fiser, A., and Sali, A. (2003). Modeller: generation and refinement of homology-based protein structure models. Methods Enzymol 374, 461-491.
  17. Sali, A., and Blundell, T.L. (1993). Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234, 779-815.
  18. Castrignano, T., De Meo, P.D., Cozzetto, D., Talamo, I.G., and Tramontano, A. (2006). The PMDB Protein Model Database. Nucleic Acids Res 34(1), D306-309.
  19. Ortiz, A.R., Strauss, C. E., Olmea, O. (2002). Mammoth (matching molecular models obtained from theory): An automated method for model comparison. Protein Sci 11(11), 2606-2621.
  20. Edgar, Robert, C. (2004). MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32(5), 1792-1797.
  21. Capra, J.A., and Singh, M. (2007). Predicting functionally important residues from sequence conservation. Bioinformatics 23, 1875-1882.
  22. Moll, M., and Kavraki, L.E. (2008). Matching of structural motifs using hashing on residue labels and geometric filtering for protein function prediction. Comput Syst Bioinformatics Conf 7, 157-168.
  23. Kim, O.T., Yura, K., and Go, N. (2006). Amino acid residue doublet propensity in the protein-RNA interface and its application to RNA interface prediction. Nucleic Acids Res 34, 6450-6460.

Cited by

  1. Genomics and Proteomics Characterization of Alphasatellite in Weed Associated with Begomovirus vol.2, pp.1, 2011,