The molecular basis of gene regulation by Nuclear Factor-κB (NF-κB) transcription factors and their coregulators is not well understood. This family of transcription factors controls a number of essential subcellular processes. Human Pirin, a nonheme iron (Fe) binding protein, has been shown to modulate the binding affinity between p65 homodimeric NF-κB and κB DNA. However, the allosteric effect of the active Fe(III) form of Pirin on the DNA has not been established. Here, we use multiple microsecond-long molecular dynamics simulations to explore the conformational dynamics of the free DNA, the p65–DNA complex, and the Pirin–p65–DNA supramolecular complex. We show that only the Fe(III) form of Pirin enhances the affinity between p65 and the DNA in the Pirin–p65–DNA supramolecular complex, in agreement with experiments. Additionally, the results provide atomistic details of the effect of the active Fe(III) form of Pirin on the DNA upon binding to the p65–DNA complex. In general, unlike the Fe(II) form of Pirin, binding of the Fe(III) form of Pirin to the p65–DNA complex significantly alters both the conformational dynamics of the DNA and the interactions between p65 and the DNA. The results provide atomic level understanding of the modulation of the DNA as a result of a redox-specific Fe(II)/Fe(III) coregulation of NF-κB by Pirin, knowledge that is necessary to fully understand normal and aberrant subcellular processes and the role of a subtle single electron redox process in gene regulation.

中文翻译：

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Pirin在NF-κB超分子复合物中对κBDNA构象动力学的氧化还原特异性变构调节。

尚不清楚核因子-κB（NF-κB）转录因子及其调节因子调控基因的分子基础。该转录因子家族控制许多必要的亚细胞过程。人皮林是一种非血红素铁（Fe）结合蛋白，已显示出它可以调节p65同型二聚体NF-κB与κBDNA之间的结合亲和力。但是，尚未确定活性的铁（III）形式的Pirin对DNA的变构作用。在这里，我们使用多个微秒长的分子动力学模拟来探索游离DNA，p65–DNA复合物和Pirin–p65–DNA超分子复合物的构象动力学。我们证明，只有铁（III）形式的Pirin才能增强p65与Pirin–p65–DNA超分子复合物中DNA的亲和力，这与实验一致。此外，结果提供了结合到p65–DNA复合物上的活性Fe（III）形式的Pirin对DNA的影响的原子学细节。通常，与Pirin的Fe（II）形式不同，Pirin的Fe（III）形式与p65-DNA复合物的结合会显着改变DNA的构象动力学以及p65和DNA之间的相互作用。该结果提供了Pirin对NF-κB的氧化还原特异性Fe（II）/ Fe（III）协同调节的结果的DNA调控的原子级理解，这是充分理解正常和异常亚细胞过程所必需的知识，并且精细的单电子氧化还原过程在基因调控中的作用。Ferin（III）形式的Pirin与p65–DNA复合物的结合会显着改变DNA的构象动力学以及p65与DNA之间的相互作用。该结果提供了Pirin对NF-κB的氧化还原特异性Fe（II）/ Fe（III）协同调节的结果的DNA调控的原子级理解，这是充分理解正常和异常亚细胞过程所必需的知识，并且精细的单电子氧化还原过程在基因调控中的作用。Ferin（III）形式的Pirin与p65–DNA复合物的结合会显着改变DNA的构象动力学以及p65与DNA之间的相互作用。该结果提供了Pirin对NF-κB的氧化还原特异性Fe（II）/ Fe（III）协同调节的结果的DNA调控的原子级理解，这是充分理解正常和异常亚细胞过程所必需的知识，并且精细的单电子氧化还原过程在基因调控中的作用。