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Nucleic Acids Research Advance Access originally published online on March 29, 2007
Nucleic Acids Research 2007 35(7):2451-2459; doi:10.1093/nar/gkm039
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Nucleic Acids Research, 2007, Vol. 35, No. 7 2451-2459
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

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

Bjørn Dalhus1,2, Ina Høydal Helle1,2, Paul H. Backe1,2, Ingrun Alseth1, Torbjørn Rognes1,3, Magnar Bjørås1,2 and Jon K. Laerdahl1,*

1Centre for Molecular Biology and Neuroscience (CMBN) and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet Medical Centre, N-0027 Oslo, Norway, 2Institute of Clinical Biochemistry, University of Oslo, N-0027 Oslo, Norway and 3Department of Informatics, University of Oslo, PO Box 1080 Blindern, N-0316 Oslo, Norway

*To whom correspondence should be addressed. Tel: +47 22844784; Fax: +47 22844782; Email: j.k.lardahl{at}medisin.uio.no

Received November 14, 2006. Revised December 20, 2006. Accepted January 8, 2007.

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.


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