Unknown

Dataset Information

0

Lesion specificity in the base excision repair enzyme hNeil1: modeling and dynamics studies.


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.

SUBMITTER: Jia L 

PROVIDER: S-EPMC2527061 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

Lesion specificity in the base excision repair enzyme hNeil1: modeling and dynamics studies.

Jia Lei L   Shafirovich Vladimir V   Geacintov Nicholas E NE   Broyde Suse S  

Biochemistry 20070414 18


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  ...[more]

Similar Datasets

| S-EPMC3096496 | biostudies-literature
| S-EPMC3683898 | biostudies-literature
| S-EPMC3430252 | biostudies-literature
| S-EPMC6154017 | biostudies-literature
| S-EPMC5096910 | biostudies-literature
| S-EPMC3582642 | biostudies-literature
| S-EPMC4964126 | biostudies-literature
| S-EPMC5693467 | biostudies-literature
| S-EPMC5159550 | biostudies-literature
| S-EPMC3479214 | biostudies-literature