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首页> 外文期刊>Biochemistry >Lesion Specificity in the Base Excision Repair Enzyme hNeill: Modeling and Dynamics Studies
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Lesion Specificity in the Base Excision Repair Enzyme hNeill: Modeling and Dynamics Studies

机译：碱基切除修复酶hNeill中的病变特异性：建模和动力学研究

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Base excision repair (BER) is the major pathway employed to excise oxidized DNA lesions. Human Neill, 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.
机译：碱基切除修复（BER）是切除氧化的DNA损伤的主要途径。人Neill是BER通路中的一种通用糖基化酶，可修复多种氧化损伤。但是，最弱的是仅切除了最普遍的8-oxo-7,8-dihydroguanine（8-oxoG）。 hNeill修复多种损伤但不修复8-oxoG的能力的结构起源是连接酶结构和损伤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，我们在与两对代表性的修复良好的底物复合物中对其进行了研究：R-和S-螺二氨基乙内酰脲（Sp）立体异构体，鸟嘌呤的非平面进一步氧化产物以及5R，6S-和5S，6R-胸腺嘧啶乙二醇（Tg）立体异构体，胸腺嘧啶最普遍的氧化损伤。我们还调查了修复不良的8-oxoG。我们采用了分子建模和10 ns分子动力学（MD）模拟。我们的研究结果为hNeill切除各种氧化性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，即嘧啶样环和共享的氢键供体-受体特性，可以使病变很好地适应在装订袋中，这有点灵活。但是，平面的8-oxoG不能很好地容纳在较浅且相对狭窄的识别袋中。它与该酶的氢键相互作用较少，并且溶剂暴露于六元环，这与该酶的较弱修复敏感性相符。

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