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

247 Scopus citations

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

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