A new model for how O6-methylguanine-DNA methyltransferase binds DNA.
Human methyltransferase (hAT) catalyzes the transfer of an alkyl group from the 6-position of guanine to an active site Cys residue. The physiological role of hAT is the repair of alkylated guanine residues in DNA. However, the repair of methylated or chloroethylated guanine bases negates the effects of certain chemotherapeutic agents. A model of how hAT binds DNA might be useful in the design of compounds that could inactivate hAT. We have used computer modeling studies to generate such a model. The model utilizes a helix-loop-wing DNA binding motif found in Mu transposase. The model incorporates a flipped out guanine base in order to bring the methylated oxygen atom close to the active site Cys residue. The model is consistent with a variety of chemical and biochemical data.
Vora
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Section of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York, USA.
Pegg
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Ealick
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D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D010583:Bacteriophage mu / Q000235:genetics; D003198:Computer Simulation; D004279:DNA, Viral / Q000378:metabolism*; D029968:Escherichia coli Proteins; D019077:Helix-Turn-Helix Motifs; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011487:Protein Conformation; D019895:Transposases
C086794:Ada-C protein, E coli; D001426:Bacterial Proteins; D004279:DNA, Viral; D029968:Escherichia coli Proteins; D010446:Peptide Fragments; D019853:O(6)-Methylguanine-DNA Methyltransferase; D019895:Transposases