ArticleBMC biochemistry2016
Conserved motif VIII of murine DNA methyltransferase Dnmt3a is essential for methylation activity.
Article in BMC biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 10 citations in OpenAlex.
- Allosteric Inhibitors of Cell-Cycle-Regulated Methyltransferase for Novel Antibiotic Development.ACS omega · 2025Article
- The Role of Protein Methyltransferases in Immunity.Molecules (Basel, Switzerland) · 2024Review
- DNA Methyltransferase 3A: A Significant Target for the Discovery of Inhibitors as Potent Anticancer Drugs.Mini reviews in medicinal chemistry · 2024Review
- Enzymology of Mammalian DNA Methyltransferases.Advances in experimental medicine and biology · 2022Article
- Understanding the R882H mutation effects of DNA methyltransferase DNMT3A: a combination of molecular dynamics simulations and QM/MM calculations.RSC advances · 2019Article
- Allosteric control of mammalian DNA methyltransferases - a new regulatory paradigm.Nucleic acids research · 2016Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDnmt3a is a DNA methyltransferase that establishes de novo DNA methylation in mammals. The structure of the Dnmt3a C-terminal domain is similar to the bacterial M. HhaI enzyme, a well-studied prokaryotic DNA methyltransferase. No X-ray structure is available for the complex of Dnmt3a with DNA and the mechanistic details of DNA recognition and catalysis by mammalian Dnmts are not completely understood.
resultsMutant variants of the catalytic domain of the murine Dnmt3a carrying substitutions of highly conserved N167, R200, and R202 have been generated by site directed mutagenesis and purified. Their methylation activity, DNA binding affinity, ability to flip the target cytosine out of the DNA double helix and covalent complex formation with DNA have been examined. Substitutions of N167 lead to reduced catalytic activity and reduced base flipping. Catalytic activity, base flipping, and covalent conjugate formation were almost completely abolished for the mutant enzymes with substitutions of R200 or R202.
conclusionsWe conclude that R202 plays a similar role in catalysis in Dnmt3a-CD as R232 in M.SssI and R165 in M.HhaI, which could be positioning of the cytosine for nucleophilic attack by a conserved Cys. R200 of Dnmt3a-CD is important in both catalysis and cytosine flipping. Both conserved R200 and R202 are involved in creating and stabilizing of the transient covalent intermediate of the methylation reaction. N167 might contribute to the positioning of the residues from the motif VI, but does not play a direct role in catalysis.
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