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首页> 外文期刊>Journal of Molecular Biology >Structure-based design of a protein immunogen that displays an HIV-1 gp41 neutralizing epitope
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Structure-based design of a protein immunogen that displays an HIV-1 gp41 neutralizing epitope

机译：展示HIV-1 gp41中和表位的蛋白质免疫原的基于结构的设计

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摘要

Antibody Z13e1 is a relatively broadly neutralizing anti-human immunodeficiency virus type 1 antibody that recognizes the membrane-proximal external region (MPER) of the human immunodeficiency virus type 1 envelope glycoprotein gp41. Based on the crystal structure of an MPER epitope peptide in complex with Z13e1 Fab, we identified an unrelated protein, interleukin (IL)-22, with a surface-exposed region that is structurally homologous in its backbone to the gp41 Z13e1 epitope. By grafting the gp41 Z13e1 epitope sequence onto the structurally homologous region in IL-22, we engineered a novel protein (Z13-IL22-2) that contains the MPER epitope sequence for use as a potential immunogen and as a reagent for the detection of Z13e1-like antibodies. The Z13-IL22-2 protein binds Fab Z13e1 with a K d of 73 nM. The crystal structure of Z13-IL22-2 in complex with Fab Z13e1 shows that the epitope region is faithfully replicated in the Fab-bound scaffold protein; however, isothermal calorimetry studies indicate that Fab binding to Z13-IL22-2 is not a lock-and-key event, leaving open the question of whether conformational changes upon binding occur in the Fab, in Z13-IL-22, or in both.
机译：抗体Z13e1是一种相对广泛的中和性抗人免疫缺陷病毒1型抗体，可识别人免疫缺陷病毒1型包膜糖蛋白gp41的膜近端外部区域（MPER）。基于与Z13e1 Fab结合的MPER表位肽的晶体结构，我们鉴定出无关蛋白，白介素（IL）-22，其表面暴露区在其骨架中与gp41 Z13e1表位在结构上是同源的。通过将gp41 Z13e1表位序列嫁接到IL-22中的结构同源区域上，我们设计了一种新型蛋白质（Z13-IL22-2），其中含有MPER表位序列，可用作潜在的免疫原和检测Z13e1的试剂样抗体。 Z13-IL22-2蛋白以73 nM的Kd结合Fab Z13e1。与Fab Z13e1复合的Z13-IL22-2的晶体结构表明，该表位区域忠实地复制在Fab结合的支架蛋白中。然而，等温量热法研究表明，Fab与Z13-IL22-2的结合不是锁键事件，这使得在Fab，Z13-IL-22或两者中结合时构象变化是否存在尚待解决。 。

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