Lesion specificity in the base excision repair enzyme hNeil1: modeling and dynamics studies.
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.
Jia
Lei
L
Department of Chemistry, New York University, 100 Washington Square East, Room 1001, New York, New York 10003, USA.
Shafirovich
Vladimir
V
Geacintov
Nicholas E
NE
Broyde
Suse
S
D003198:Computer Simulation; D045647:DNA Glycosylases / Q000737:chemistry* / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006151:Guanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018384:Oxidative Stress; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013237:Stereoisomerism; D013379:Substrate Specificity; D013816:Thermodynamics
D004268:DNA-Binding Proteins; D011743:Pyrimidines; D013141:Spiro Compounds; C408822:spiroiminodihydantoin; D006151:Guanosine; C046215:8-hydroxyguanosine; D045647:DNA Glycosylases; C473634:NEIL1 protein, human