Structural basis for the excision repair of alkylation-damaged DNA

Cell. 1996 Jul 26;86(2):321-9. doi: 10.1016/s0092-8674(00)80103-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylation
  • Amino Acid Sequence
  • Conserved Sequence
  • Crystallization
  • DNA Damage / physiology*
  • DNA Glycosylases
  • DNA Repair / physiology*
  • DNA, Bacterial / genetics*
  • DNA-Binding Proteins / chemistry
  • Escherichia coli / chemistry
  • Escherichia coli / enzymology
  • Image Processing, Computer-Assisted
  • Molecular Sequence Data
  • N-Glycosyl Hydrolases / chemistry*
  • N-Glycosyl Hydrolases / genetics
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Tertiary

Substances

  • DNA, Bacterial
  • DNA-Binding Proteins
  • DNA Glycosylases
  • N-Glycosyl Hydrolases
  • DNA-3-methyladenine glycosidase II