Bacterial DNA Methyltransferases
DNA methylation in bacteria is widespread and in some cases essential. Our current focus is on “orphan” enzymes which do not have a cognate endonuclease, such as the Cell Cycle Regulated Methyltransferase (CcrM), found C. crescentus, and is essential for viability. Our recent cocrystal structure shows this enzyme displays an entirely new DNA recognition mechanism by separating the two strands of its target sequence (GANTC) and methylating the adenine. Even more amazing is that this process leads to an unprecedented level of sequence discrimination, resulting in fewer than one in ten million mistakes. The structural features we observe in the cocrystal structure are found in many bacterial enzymes, including numerous human pathogens. Our interest is to develop antibiotics that target these enzymes.
Related Publications
Cell cycle regulated DNA methyltransferase: fluorescent tracking of a DNA strand-separation mechanism and identification of the responsible protein motif
Konttinen O, Carmody J, Pathuri S, Anderson K, Zhou X, Reich NO. Nucleic Acids Res., 48(20) (2020), 11589-11601
https://doi.org/10.1093/nar/gkaa844
The cell cycle-regulated DNA adenine methyltransferase CcrM opens a bubble at its DNA recognition site
Horton JR, Woodcock CB, Opot SB, Reich NO, Zhang X, Cheng X. Nat. Commun., 10(1) (2019), 4600
https://doi.org/10.1038/s41467-019-12498-7
The highly specific, cell cycle\[Dash]regulated methyltransferase from Caulobacter crescentus relies on a novel DNA recognition mechanism
Reich NO, Dang E, Kurnik M, Pathuri S, Woodcock CB. J. Biol. Chem., 293(49) (2018), 19038-19046
https://doi.org/10.1074/jbc.RA118.005212
Caulobacter crescentus Cell Cycle-Regulated DNA Methyltransferase Uses a Novel Mechanism for Substrate Recognition
Woodcock CB, Yakubov AB, Reich NO. Biochemistry-US, 56(30) (2017), 3913-3922
https://doi.org/10.1021/acs.biochem.7b00378
Selective Inhibitors of Bacterial DNA Adenine Methyltransferases
Mashhoon N, Pruss C, Carroll M, Johnson PH, Reich NO. J. Biomol. Screen, 11(5) (2006), 497-510
https://doi.org/10.1177/1087057106287933
