来自美国斯坦福大学医学院和瑞士伯尔尼大学的研究人员在新研究中证实一种人造分子可破坏引起过敏性反应的复合物,并揭示了相关机制,这一研究发现有可能导致开发出针对许多急性过敏性反应高效、快速的干预治疗。

-2012年11月22日《自然》

中文翻译


【题目】破坏性的大分子抑制剂加速分解IgE受体复合物

【译文】IgE抗体结合高亲和力的IgE Fc受体(FcεRI),主要被发现在肥大细胞和嗜碱性粒细胞中,并会触发过敏反应的炎症级联作用。IgE–FcεRI结合的抑制剂已经被鉴定出来,一种抗IgE治疗性抗体(omalizumab)常用于治疗急性过敏性哮喘。然而,在过敏原暴露之前引导细胞的完整IgE–FcεRI复合物分解极其缓慢,且不能被竞争性抑制剂所破坏。IgE-Fc构象灵活性表明抑制作用可能是由变构效应或其他非典型机制所介导的。本研究证实了一种人工蛋白抑制剂DARPin E2_79可以通过非典型抑制机制发挥作用,不仅能阻断IgE–FcεRI相互作用,还可以活跃地刺激配体-受体复合物的分解。E2_79–IgE-Fc3-4复合物的结构预测了不对称IgE–FcεRI复合物中两种非等价E2_79位点的存在,位点1远离受体而位点2则表现出局部空间重叠的现象。尽管该结构是一种变构抑制机制的预示,但突变研究和定量动态模型表明E2_79是通过一种单独为位于位点2的便利分解机制的。这些结果证实了高亲和力的IgE–FcεRI复合物可被积极地分解以阻断过敏反应,并表明蛋白-蛋白复合物可能更加普遍顺从于大分子抑制剂产生的主动破坏。

英文原稿


[Title]: Accelerated disassembly of IgE–receptor complexes by a disruptive macromolecular inhibitor

[Authors]:Beomkyu Kim,1, 4 Alexander Eggel,2, 4 Svetlana S. Tarchevskaya,1 Monique Vogel,2 Heino Prinz3 & Theodore S. Jardetzky1

[Abstract]IgE antibodies bind the high-affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE–FcεRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE–FcεRI complexes that prime cells before allergen exposure dissociate extremely slowly and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms. Here we demonstrate that an engineered protein inhibitor, DARPin E2_79, acts through a non-classical inhibition mechanism, not only blocking IgE–FcεRI interactions, but actively stimulating the dissociation of preformed ligand–receptor complexes. The structure of the E2_79–IgE-Fc3-4 complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE–FcεRI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE–FcεRI complexes can be actively dissociated to block the allergic response and suggest that protein–protein complexes may be more generally amenable to active disruption by macromolecular inhibitors.

原文地址

http://www.nature.com/nature/journal/v491/n7425/full/nature11546.html

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