Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA: Mechanisms for nucleotide flipping and base excision

Albert Y Lau, Orlando D. Schärer, Leona Samson, Gregory L. Verdine, Tom Ellenberger

Research output: Contribution to journalArticle

Abstract

DNA N-glycosylases are base excision-repair proteins that locate and cleave damaged bases from DNA as the first step in restoring the genetic blueprint. The human enzyme 3-methyladenine DNA glycosylase removes a diverse group of damaged bases from DNA, including cytotoxic and mutagenic alkylation adducts of purines. We report the crystal structure of human 3-methyladenine DNA glycosylase complexed to a mechanism-based pyrrolidine inhibitor. The enzyme has intercalated into the minor groove of DNA, causing the abasic pyrrolidine nucleotide to flip into the enzyme active site, where a bound water is poised for nucleophilic attack. The structure shows an elegant means of exposing a nucleotide for base excision as well as a network of residues that could catalyze the in-line displacement of a damaged base from the phosphodeoxyribose backbone.

Original languageEnglish (US)
Pages (from-to)249-258
Number of pages10
JournalCell
Volume95
Issue number2
DOIs
StatePublished - Oct 16 1998
Externally publishedYes

Fingerprint

3-methyladenine-DNA glycosylase
DNA Repair Enzymes
Nucleotides
Crystal structure
DNA
Enzymes
DNA Glycosylases
Purines
Alkylation
Blueprints
DNA Repair
Catalytic Domain
Repair
Water
Proteins
pyrrolidine

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA : Mechanisms for nucleotide flipping and base excision. / Lau, Albert Y; Schärer, Orlando D.; Samson, Leona; Verdine, Gregory L.; Ellenberger, Tom.

In: Cell, Vol. 95, No. 2, 16.10.1998, p. 249-258.

Research output: Contribution to journalArticle

Lau, Albert Y ; Schärer, Orlando D. ; Samson, Leona ; Verdine, Gregory L. ; Ellenberger, Tom. / Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA : Mechanisms for nucleotide flipping and base excision. In: Cell. 1998 ; Vol. 95, No. 2. pp. 249-258.
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