Lesion specificity in the base excision repair enzyme hNeil1

Modeling and dynamics studies

Lei Jia, Vladimir Shafirovich, Nicholas Geacintov, Suse Broyde

Research output: Contribution to journalArticle

Abstract

Base excision repair (BER) is the major pathway employed to excise oxidized DNA lesions. Human Neil1, a versatile glycosylase in the BER pathway, repairs a diverse array of oxidative lesions; however, the most prevalent, 8-oxo-7,8-dihydroguanine (8-oxoG), is only weakly excised. The structural origin of hNeil1's ability to repair a variety of lesions but not 8-oxoG is a model system for connecting enzyme structure and lesion-recognition specificity. To elucidate structural properties determining hNeil1's substrate specificities, we have investigated it in complex with two pairs of representative well-repaired substrates: the R- and S-spiroiminodihydantoin (Sp) stereoisomers, nonplanar further oxidation products of guanine, and the 5R,6S- and 5S,6R-thymine glycol (Tg) stereoisomers, the most prevalent oxidative lesions of thymine. We also investigate the poorly repaired 8-oxoG. We employed molecular modeling and 10 ns molecular dynamics (MD) simulations. The results of our investigations provide structural explanations for the ability of hNeil1 to excise a variety of oxidative lesions: they possess common chemical features, namely, a pyrimidine-like ring and shared hydrogen bond donor - acceptor properties, which allow the lesions to fit well in the binding pocket, which is somewhat flexible. However, the planar 8-oxoG is not as well accommodated in the shallow and comparatively cramped recognition pocket; it has fewer hydrogen bonding interactions with the enzyme and a solvent exposed six-membered ring, consistent with its poor repair susceptibility by this enzyme.

Original languageEnglish (US)
Pages (from-to)5305-5314
Number of pages10
JournalBiochemistry
Volume46
Issue number18
DOIs
StatePublished - May 8 2007

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DNA Repair
Repair
Stereoisomerism
Enzymes
Hydrogen bonds
Thymine
Guanine
Molecular Dynamics Simulation
Hydrogen Bonding
Substrate Specificity
Molecular modeling
Hydrogen
Substrates
Molecular dynamics
Structural properties
8-hydroxyguanine
DNA
Oxidation
Computer simulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Lesion specificity in the base excision repair enzyme hNeil1 : Modeling and dynamics studies. / Jia, Lei; Shafirovich, Vladimir; Geacintov, Nicholas; Broyde, Suse.

In: Biochemistry, Vol. 46, No. 18, 08.05.2007, p. 5305-5314.

Research output: Contribution to journalArticle

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