Lesion specificity in the base excision repair enzyme hNeil1: Modeling and dynamics studies
Lesion specificity in the base excision repair enzyme hNeil1: Modeling and dynamics studies
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DOI：
10.1021/bi062269m
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发表时间：
2007-05-08
期刊：
影响因子：
2.9
通讯作者：
Broyde, Suse
中科院分区：
文献类型：
--
作者：
Jia, Lei;Shafirovich, Vladimir;Broyde, Suse
碱基切除修复(BER)是切除氧化DNA损伤的主要途径。人类NEIL1是BER途径中的一种多功能糖基酶，它修复了一系列不同的氧化损伤；然而，最普遍的8-氧-7，8-二氢鸟嘌呤(8-oxoG)只被微弱地切除。HNeill修复各种损伤而不是8-oxoG的能力的结构起源是一个连接酶结构和病变识别特异性的模型系统。为了阐明决定hNeill底物特异性的结构性质，我们研究了它与两对修复良好的具有代表性的底物的复合体：R-和S-螺亚胺二乙内酰脲(Sp)立体异构体，鸟嘌呤的非平面进一步氧化产物，以及胸腺嘧啶最常见的氧化损伤-5R，6S-和5S，6R-胸腺嘧啶二醇(TG)立体异构体。我们还调查了修复不良的8-oxoG。我们采用了分子模拟和10 ns分子动力学(MD)模拟。我们的研究结果为hNeill切除各种氧化损伤的能力提供了结构上的解释：它们具有共同的化学特征，即类似嘧啶的环和共享的氢键供体-受体属性，这使得损伤能够很好地适合结合口袋，这在某种程度上是灵活的。然而，平面8-oxoG不能很好地容纳在较浅和相对狭窄的识别口袋中；它与酶的氢键相互作用较少，并且有一个暴露在溶剂中的六元环，这与它对这种酶的修复敏感性很差是一致的。
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 hNeill'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 hNeill'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 hNeill 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.