Homology modeling and function prediction of hABH1, involving in repair of alkylation damaged DNA.

Inhibition of DNA repair mechanism through alkylating agents in tumor cells is an important method for cancer treatment. Alkylation damage repair gene AlkB was first reported in E. coli. In human and other mammals eight distinguishing homologs of AlkB were detected and are known as hABH1 to hABH8. Crystal structures of hABH2 and hABH3 elucidated the role of human AlkB homologs involved in DNA and RNA repair pathways. No crystal structure of hABH1 is available for the detailed study on the nature and function of the molecule. In the present work we performed homology modeling and different tertiary structure based study on human AlkB homolog hABH1. hABH1.B99990005.pdb, out of five models generated using the program modeler 9v7 and validated with Ramachandran plot showed that 97.9% residues were in the favored and additional allowed region and less residues in disallowed region, which is the best among all models. Functions of the selected model were studied in terms of cation binding, transition metal ion binding and metal ion binding function with oxidoreductase activity. Two functional sites and one conserved cluster were detected in the protein. Ligand binding residue prediction showed four ligand clusters with 17 ligands in cluster 1. In this cluster seven Fe(2+) heterogen counts were detected. Most significantly, predicted iron-binding motif in hABH1 was found as His231-X-Asp233-XnHis287 which corresponds to His131-XAsp133-Xn-His187 in AlkB of E. coli homologue. This shows the similar pattern of aspartic acid and histidine residues in the functional part of the protein both in human and E. coli. These results can be used further to design inhibitors aiding chemotherapy and cancer related diseases.