title: Structural basis for the excision repair of alkylation-damaged DNA.
abstract: Base-excision DNA repair proteins that target alkylation damage act on a variety of seemingly dissimilar adducts, yet fail to recognize other closely related lesions. The 1.8 A crystal structure of the monofunctional DNA glycosylase AlkA (E. coli 3-methyladenine-DNA glycosylase II) reveals a large hydrophobic cleft unusually rich in aromatic residues. An Asp residue projecting into this cleft is essential for catalysis, and it governs binding specificity for mechanism-based inhibitors. We propose that AlkA recognizes electron-deficient methylated bases through pi-donor/acceptor interactions involving the electron-rich aromatic cleft. Remarkably, AlkA is similar in fold and active site location to the bifunctional glycosylase/lyase endonuclease III, suggesting the two may employ fundamentally related mechanisms for base excision.
authors.affiliation: Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, Boston, Massachusetts02115, USA.
authors.forename: J
authors.initials: J
authors.lastname: Labahn
authors.forename: O D
authors.initials: OD
authors.lastname: Schärer
authors.forename: A
authors.initials: A
authors.lastname: Long
authors.forename: K
authors.initials: K
authors.lastname: Ezaz-Nikpay
authors.forename: G L
authors.initials: GL
authors.lastname: Verdine
authors.forename: T E
authors.initials: TE
authors.lastname: Ellenberger
mesh_terms: D000478:Alkylation; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D003460:Crystallization; D004249:DNA Damage / Q000502:physiology*; D045647:DNA Glycosylases; D004260:DNA Repair / Q000502:physiology*; D004269:DNA, Bacterial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology; D007091:Image Processing, Computer-Assisted; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C076131:DNA-3-methyladenine glycosidase II