title: Establishment and functional validation of a structural homology model for human DNA methyltransferase 1.
abstract: Changes in DNA methylation patterns play an important role in tumorigenesis. The DNA methyltransferase 1 (DNMT1) protein represents a major DNA methyltransferase activity in human cells and is therefore a prominent target for experimental cancer therapies. However, there are only few available inhibitors and their high toxicity and low specificity have so far precluded their broad use in chemotherapy. Based on the strong conservation of catalytic DNA methyltransferase domains we have used a homology modeling approach to determine the three-dimensional structure of the DNMT1 catalytic domain. Our results suggest an overall structural conservation with other DNA methyltransferases but also indicate local conformational differences. To prove the validity of our model we used it as a template to design a novel derivative of the known DNA methyltransferase inhibitor 5-azacytidine. The resulting compound (N4-fluoroacetyl-5-azacytidine) functioned as an efficient inhibitor of DNA methylation in human tumor cell lines and also provides novel opportunities for pharmacological applications.
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Siedlecki
authors.forename: Regine
authors.initials: R
authors.lastname: Garcia Boy
authors.forename: Slobodan
authors.initials: S
authors.lastname: Comagic
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
authors.forename: Manfred
authors.initials: M
authors.lastname: Wiessler
authors.forename: Piotr
authors.initials: P
authors.lastname: Zielenkiewicz
authors.forename: Sandor
authors.initials: S
authors.lastname: Suhai
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
mesh_terms: D000595:Amino Acid Sequence; D001374:Azacitidine / Q000494:pharmacology; D020134:Catalytic Domain; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D001374:Azacitidine