Nucleic Acids Res 29(18): 3784-3795

AdoMet-dependent methylation, DNA methyltransferases and base flipping

Emory University School of Medicine, Department of Biochemistry, 1510 Clifton Road, Atlanta, GA 30322, USA and ^{New England Biolabs, 32 Tozer Road, Beverly, MA 01915, USA}

^{To whom correspondence should be addressed. Tel: +1 404 727 8491; Fax: +1 404 727 3746; Email:}ude.yrome@gnehcx

Received 2001 Feb 5; Revised 2001 Mar 19; Accepted 2001 Mar 19.

Abstract

Twenty AdoMet-dependent methyltransferases (MTases) have been characterized structurally by X-ray crystallography and NMR. These include seven DNA MTases, five RNA MTases, four protein MTases and four small molecule MTases acting on the carbon, oxygen or nitrogen atoms of their substrates. The MTases share a common core structure of a mixed seven-stranded β-sheet (6↓ 7↑ 5↓ 4↓ 1↓ 2↓ 3↓) referred to as an ‘AdoMet-dependent MTase fold’, with the exception of a protein arginine MTase which contains a compact consensus fold lacking the antiparallel hairpin strands (6↓ 7↑). The consensus fold is useful to identify hypothetical MTases during structural proteomics efforts on unannotated proteins. The same core structure works for very different classes of MTase including those that act on substrates differing in size from small molecules (catechol or glycine) to macromolecules (DNA, RNA and protein). DNA MTases use a ‘base flipping’ mechanism to deliver a specific base within a DNA molecule into a typically concave catalytic pocket. Base flipping involves rotation of backbone bonds in double-stranded DNA to expose an out-of-stack nucleotide, which can then be a substrate for an enzyme-catalyzed chemical reaction. The phenomenon is fully established for DNA MTases and for DNA base excision repair enzymes, and is likely to prove general for enzymes that require access to unpaired, mismatched or damaged nucleotides within base-paired regions in DNA and RNA. Several newly discovered MTase families in eukaryotes (DNA 5mC MTases and protein arginine and lysine MTases) offer new challenges in the MTase field.

Abstract

^{The coordinates of MUG–DNA complexes are currently not available in PDB.}

ACKNOWLEDGEMENTS

We thank Dr Alan M. Friedman for providing PIMT coordinates, Drs Mark A. Saper and Ursula Jakob for FTSJ coordinates, Drs Dick Gumport and Mair Churchill for M.RsrI coordinates, Dr Osnat Herzberg for communicating results before publication, and Drs Venki Ramakrishnan and Andrew Carter for providing images for Figure 6. Work in our laboratories is supported by grants from the National Institutes of Health (GM46127 to R.J.R. and GM49245 and GM61355 to X.C.).

ACKNOWLEDGEMENTS

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