A Novel Allosteric Mechanism of NF-κB Dimerization and DNA Binding Targeted by an Anti-Inflammatory Drug
A Novel Allosteric Mechanism of NF-κB Dimerization and DNA Binding Targeted by an Anti-Inflammatory Drug
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DOI：
10.1128/mcb.00895-15
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发表时间：
2016-04-01
影响因子：
5.3
通讯作者：
Dikstein, Rivka
中科院分区：
文献类型：
--
作者：
Ashkenazi, Shaked;Plotnikov, Alexander;Dikstein, Rivka
NF-κ B家族在免疫和应激反应中起关键作用，其失调导致多种疾病。因此，它的调节已成为一个重要的治疗目标。在这里，我们使用高通量筛选直接抑制NF-κ B蛋白p65二聚化的小分子。其中一种已鉴定的抑制剂是醉茄素A（WFA），一种有文献记载的抗癌和抗炎化合物。计算模型表明，WFA接触的二聚界面上的一个亚基和表面残基E285和Q287的其他。尽管它们的位置远离二聚化位点，但E285和Q287取代减少了二聚化和WFA效应。进一步的研究表明，它们对二聚化的影响与它们接近保守的疏水核心结构域（HCD）有关，该结构域对二聚化和DNA结合至关重要。我们的研究结果确立了NF-κ B二聚化作为药物靶点，并揭示了一个变构域作为WFA作用的靶点。
The NF-kappa B family plays key roles in immune and stress responses, and its deregulation contributes to several diseases. Therefore its modulation has become an important therapeutic target. Here, we used a high-throughput screen for small molecules that directly inhibit dimerization of the NF-kappa B protein p65. One of the identified inhibitors is withaferin A (WFA), a documented anticancer and anti-inflammatory compound. Computational modeling suggests that WFA contacts the dimerization interface on one subunit and surface residues E285 and Q287 on the other. Despite their locations far from the dimerization site, E285 and Q287 substitutions diminished both dimerization and the WFA effect. Further investigation revealed that their effects on dimerization are associated with their proximity to a conserved hydrophobic core domain (HCD) that is crucial for dimerization and DNA binding. Our findings established NF-kappa B dimerization as a drug target and uncovered an allosteric domain as a target of WFA action.