Modulating DNA by polyamides to regulate transcription factor PU.1-DNA binding interactions.,Biochimie

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Modulating DNA by polyamides to regulate transcription factor PU.1-DNA binding interactions.
Biochimie ( IF 3.3 ) Pub Date : 2019-08-21 , DOI: 10.1016/j.biochi.2019.08.009
Beibei Liu ₁ , James K Bashkin ₂ , Gregory M K Poon ₁ , Shuo Wang ₁ , Siming Wang ₁ , W David Wilson ₁

Affiliation

Hairpin polyamides are synthetic small molecules that bind DNA minor groove sequence-selectively and, in many sequences, induce widening of the minor groove and compression of the major groove. The structural distortion of DNA caused by polyamides has enhanced our understanding of the regulation of DNA-binding proteins via polyamides. Polyamides have DNA binding affinities that are comparable to those proteins, therefore, can potentially be used as therapeutic agents to treat diseases caused by aberrant gene expression. In fact, many diseases are characterized by over- or under-expressed genes. PU.1 is a transcription factor that regulates many immune system genes. Aberrant expression of PU.1 has been associated with the development of acute myeloid leukemia (AML). We have, therefore, designed and synthesized ten hairpin polyamides to investigate their capacity in controlling the PU.1-DNA interaction. Our results showed that nine of the polyamides disrupt PU.1-DNA binding and the inhibition capacity strongly correlates with binding affinity. One molecule, FH1024, was observed forming a FH1024-PU.1-DNA ternary complex instead of inhibiting PU.1-DNA binding. This is the first report of a small molecule that is potentially a weak agonist that recruits PU.1 to DNA. This finding sheds light on the design of polyamides that exhibit novel regulatory mechanisms on protein-DNA binding.

中文翻译：

通过聚酰胺调节 DNA 以调节转录因子 PU.1-DNA 结合相互作用。

发夹聚酰胺是合成小分子，可选择性地结合 DNA 小沟序列，并在许多序列中诱导小沟加宽和大沟压缩。由聚酰胺引起的 DNA 结构扭曲增强了我们对通过聚酰胺调节 DNA 结合蛋白的理解。聚酰胺具有与这些蛋白质相当的 DNA 结合亲和力，因此有可能用作治疗剂来治疗由异常基因表达引起的疾病。事实上，许多疾病的特征是基因过度表达或表达不足。PU.1 是一种调节许多免疫系统基因的转录因子。PU.1 的异常表达与急性髓性白血病 (AML) 的发展有关。因此，我们有设计并合成了十种发夹聚酰胺，以研究它们控制 PU.1-DNA 相互作用的能力。我们的结果表明，九种聚酰胺破坏了 PU.1-DNA 结合，抑制能力与结合亲和力密切相关。观察到一个分子 FH1024 形成 FH1024-PU.1-DNA 三元复合物而不是抑制 PU.1-DNA 结合。这是小分子的第一份报告，该小分子可能是一种将 PU.1 募集到 DNA 的弱激动剂。这一发现揭示了对蛋白质-DNA 结合表现出新的调节机制的聚酰胺的设计。1-DNA 三元复合物而不是抑制 PU.1-DNA 结合。这是小分子的第一份报告，该小分子可能是一种将 PU.1 募集到 DNA 的弱激动剂。这一发现揭示了对蛋白质-DNA 结合表现出新的调节机制的聚酰胺的设计。1-DNA 三元复合物而不是抑制 PU.1-DNA 结合。这是小分子的第一份报告，该小分子可能是一种将 PU.1 募集到 DNA 的弱激动剂。这一发现揭示了对蛋白质-DNA 结合表现出新的调节机制的聚酰胺的设计。

更新日期：2019-08-21

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