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Nucleic Acids Res. 2007;35(7):2451-9. Epub 2007 Mar 29.

Structural insight into repair of alkylated DNA by a new superfamily of DNA glycosylases comprising HEAT-like repeats.

Author information

1
Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet Medical Centre, Oslo, Norway.

Abstract

3-methyladenine DNA glycosylases initiate repair of cytotoxic and promutagenic alkylated bases in DNA. We demonstrate by comparative modelling that Bacillus cereus AlkD belongs to a new, fifth, structural superfamily of DNA glycosylases with an alpha-alpha superhelix fold comprising six HEAT-like repeats. The structure reveals a wide, positively charged groove, including a putative base recognition pocket. This groove appears to be suitable for the accommodation of double-stranded DNA with a flipped-out alkylated base. Site-specific mutagenesis within the recognition pocket identified several residues essential for enzyme activity. The results suggest that the aromatic side chain of a tryptophan residue recognizes electron-deficient alkylated bases through stacking interactions, while an interacting aspartate-arginine pair is essential for removal of the damaged base. A structural model of AlkD bound to DNA with a flipped-out purine moiety gives insight into the catalytic machinery for this new class of DNA glycosylases.

PMID:
17395642
PMCID:
PMC1874660
DOI:
10.1093/nar/gkm039
[Indexed for MEDLINE]
Free PMC Article

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