期刊
EMBO JOURNAL
卷 22, 期 19, 页码 4898-4909出版社
WILEY
DOI: 10.1093/emboj/cdg505
关键词
3-methyladenine; base excision; DNA repair; glycosylase; helix-hairpin-helix
资金
- NIGMS NIH HHS [F32 GM065714-01, F32 GM065714, R01 GM052504, F32 GM065714-02, R01-GM52504] Funding Source: Medline
DNA glycosylases catalyze the excision of chemically modified bases from DNA. Although most glycosylases are specific to a particular base, the 3-methyladenine (m(3)A) DNA glycosylases include both highly specific enzymes acting on a single modified base, and enzymes with broader specificity for alkylation-damaged DNA. Our structural understanding of these different enzymatic specificities is currently limited to crystal and NMR structures of the unliganded enzymes and complexes with abasic DNA inhibitors. Presented here are high-resolution crystal structures of the m(3)A DNA glycosylase from Helicobacter pylori (MagIII) in the unliganded form and bound to alkylated bases 3,9-dimethyladenine and 1,N-6-ethenoadenine. These are the first structures of a nucleobase bound in the active site of a m(3)A glycosylase belonging to the helix-hairpin-helix superfamily. MagIII achieves its specificity for positively-charged m(3)A not by direct interactions with purine or methyl substituent atoms, but rather by stacking the base between two aromatic side chains in a pocket that excludes 7-methylguanine. We report base excision and DNA binding activities of MagIII active site mutants, together with a structural comparison of the HhH glycosylases.
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