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Designed proteins assemble antibodies into modular nanocages
Science ( IF 56.9 ) Pub Date : 2021-04-02 , DOI: 10.1126/science.abd9994
Robby Divine 1, 2 , Ha V Dang 1 , George Ueda 1, 2 , Jorge A Fallas 1, 2 , Ivan Vulovic 1, 2 , William Sheffler 2 , Shally Saini 1, 3 , Yan Ting Zhao 1, 3, 4 , Infencia Xavier Raj 1, 3 , Peter A Morawski 5 , Madeleine F Jennewein 6 , Leah J Homad 6 , Yu-Hsin Wan 6 , Marti R Tooley 2 , Franziska Seeger 1, 2 , Ali Etemadi 2, 7 , Mitchell L Fahning 5 , James Lazarovits 1, 2 , Alex Roederer 2 , Alexandra C Walls 1 , Lance Stewart 2 , Mohammadali Mazloomi 7 , Neil P King 1, 2 , Daniel J Campbell 5 , Andrew T McGuire 6, 8 , Leonidas Stamatatos 6, 8 , Hannele Ruohola-Baker 1, 3 , Julie Mathieu 3, 9 , David Veesler 1 , David Baker 1, 2, 10
Affiliation  

Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)–mediated apoptosis, angiopoietin-1 receptor (Tie2)–mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc–angiotensin-converting enzyme 2 (ACE2) fusion proteins.



中文翻译:

设计的蛋白质将抗体组装成模块化纳米笼

受体接合抗体或配体的多价展示可以增强它们的活性。在这里,我们不是通过附着到预先存在的支架上来实现多价,而是通过纳米笼的计算设计将形式和功能结合起来,其中一个结构成分是抗体或Fc配体融合体,第二个是设计的驱动纳米笼的抗体结合同源寡聚物集会。通过电子显微镜确定的八个纳米笼的结构,跨越二面体、四面体、八面体和二十面体结构,每个纳米笼分别有 2、6、12 和 30 个抗体,与相应的计算模型非常匹配。与游离抗体或 Fc 融合体相比,靶向细胞表面受体的抗体纳米笼可增强死亡受体 5 (DR5) 介导的细胞凋亡、血管生成素 1 受体 (Tie2) 介导的血管生成、CD40 激活和 T 细胞增殖中的信号传导。Nanocage 组装还通过 α-SARS-CoV-2 单克隆抗体和 Fc-血管紧张素转换酶 2 (ACE2) 融合蛋白增强严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 假病毒的中和作用。

更新日期:2021-04-02
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