Role of Structural Dynamics in Selectivity and Mechanism of Non-heme Fe(II) and 2-Oxoglutarate-Dependent Oxygenases Involved in DNA Repair.,ACS Central Science

当前位置： X-MOL 学术 › ACS Cent. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Role of Structural Dynamics in Selectivity and Mechanism of Non-heme Fe(II) and 2-Oxoglutarate-Dependent Oxygenases Involved in DNA Repair.
ACS Central Science ( IF 12.7 ) Pub Date : 2020-05-08 , DOI: 10.1021/acscentsci.0c00312
Sodiq O Waheed ₁ , Rajeev Ramanan ₁ , Shobhit S Chaturvedi ₁ , Nicolai Lehnert ₂ , Christopher J Schofield ₃ , Christo Z Christov ₁ , Tatyana G Karabencheva-Christova ₁

Affiliation

AlkB and its human homologue AlkBH2 are Fe(II)- and 2-oxoglutarate (2OG)-dependent oxygenases that repair alkylated DNA bases occurring as a consequence of reactions with mutagenic agents. We used molecular dynamics (MD) and combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate how structural dynamics influences the selectivity and mechanisms of the AlkB- and AlkBH2-catalyzed demethylation of 3-methylcytosine (m₃C) in single (ssDNA) and double (dsDNA) stranded DNA. Dynamics studies reveal the importance of the flexibility in both the protein and DNA components in determining the preferences of AlkB for ssDNA and of AlkBH2 for dsDNA. Correlated motions, including of a hydrophobic β-hairpin, are involved in substrate binding in AlkBH2–dsDNA. The calculations reveal that 2OG rearrangement prior to binding of dioxygen to the active site Fe is preferred over a ferryl rearrangement to form a catalytically productive Fe(IV)═O intermediate. Hydrogen atom transfer proceeds via a σ-channel in AlkBH2–dsDNA and AlkB–dsDNA; in AlkB–ssDNA, there is a competition between σ- and π-channels, implying that the nature of the complexed DNA has potential to alter molecular orbital interactions during the substrate oxidation. Our results reveal the importance of the overall protein–DNA complex in determining selectivity and how the nature of the substrate impacts the mechanism.

中文翻译：

结构动力学在参与 DNA 修复的非血红素 Fe(II) 和 2-氧化戊二酸依赖性加氧酶的选择性和机制中的作用。

AlkB 及其人类同源物 AlkBH2 是 Fe(II) 和 2-氧化戊二酸 (2OG) 依赖性加氧酶，可修复因与诱变剂反应而发生的烷基化 DNA 碱基。我们使用分子动力学 (MD) 和组合量子力学/分子力学 (QM/MM) 方法来研究结构动力学如何影响 AlkB 和 AlkBH2 催化 3-甲基胞嘧啶 (m ₃ C) 去甲基化的选择性和机制。（ssDNA）和双链（dsDNA）DNA。动力学研究揭示了蛋白质和 DNA 成分的灵活性在确定 AlkB 对 ssDNA 的偏好和 AlkBH2 对 dsDNA 的偏好方面的重要性。相关运动，包括疏水性 β-发夹的运动，参与 AlkBH2-dsDNA 中的底物结合。计算表明，在双氧与活性位点 Fe 结合之前进行 2OG 重排优于 Ferry1 重排，以形成催化生产的 Fe(IV)=O 中间体。氢原子转移通过 AlkBH2–dsDNA 和 AlkB–dsDNA 中的 σ 通道进行；在 AlkB-ssDNA 中，σ 通道和 π 通道之间存在竞争，这意味着复合 DNA 的性质有可能改变底物氧化过程中的分子轨道相互作用。我们的结果揭示了整个蛋白质-DNA 复合物在决定选择性方面的重要性以及底物性质如何影响该机制。

更新日期：2020-05-08

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11