Ashkenazi Shaked, Plotnikov Alexander, Bahat Anat, Ben-Zeev Efrat, Warszawski Shira, Dikstein Rivka
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
The Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot, Israel.
Mol Cell Biol. 2016 Mar 31;36(8):1237-47. doi: 10.1128/MCB.00895-15. Print 2016 Apr.
The NF-κB 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-κB 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-κB dimerization as a drug target and uncovered an allosteric domain as a target of WFA action.
核因子-κB（NF-κB）家族在免疫和应激反应中发挥关键作用，其失调会导致多种疾病。因此，对其进行调控已成为一个重要的治疗靶点。在此，我们针对直接抑制NF-κB蛋白p65二聚化的小分子进行了高通量筛选。所鉴定出的抑制剂之一是白英素A（WFA），一种已被记载的抗癌和抗炎化合物。计算模型表明，WFA与一个亚基上的二聚化界面以及另一个亚基上的表面残基E285和Q287接触。尽管E285和Q287的位置远离二聚化位点，但它们的取代减少了二聚化以及WFA的作用。进一步研究表明，它们对二聚化的影响与其靠近一个对二聚化和DNA结合至关重要的保守疏水核心结构域（HCD）有关。我们的研究结果确立了NF-κB二聚化作为一个药物靶点，并揭示了一个变构结构域作为WFA作用的靶点。
