A homology model of the three-dimensional structure of human O6-alkylguanine-DNA alkyltransferase based on the crystal structure of the C-terminal domain of the Ada protein from Escherichia coli

J. E.A. Wibley, Y. H. McKie, E. Embrey, D. S. Marks, K. T. Douglas*, M. H. Moore, P. C.E. Moody

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

O6-Alkylguanine-DNA alkyltransferase (EC 2.1.1.63) repairs O6-alkylguanine lesions in DNA. A homology model of the human protein (hAT) was built, based on the crystal structure of the C-terminal domain of the Ada protein, which carries out a similar repair in Escherichia coli. Sequence alignments of known 06-alkylguanine-DNA alkyltransferases were used to aid the model building using QUANTA and CHARMm software. Despite low homology in the N-terminal half (hAT residues 1-85), a well-defined topology over this region in Ada permitted successful modelling. The C-terminal half of hAT (residues 92-207) was modelled almost entirely by residue-for-residue superposition onto the Ada structure up to residue hAT175 The model was solvated to a residue radius of 0.8 Å and then minimized using CHARMm. This structural model was used to rationalize findings from site-directed mutagenesis experiments on hAT, to make further predictions on the relationship between structure and function for the alkyltransferase family of proteins, and to explain the specificity towards known small-molecule inhibitors of the protein.

Original languageEnglish
Pages (from-to)75-95
Number of pages21
JournalAnti-Cancer Drug Design
Volume10
Issue number1
Publication statusPublished - Jan 1995

Keywords

  • Ada protein
  • alkyltransferase
  • DNA repair
  • homology modelling
  • mutagenesis
  • O-alkylguanine
  • O-methylguanine

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