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首页> 外文期刊>Journal of Molecular Biology >Highly specific anti-estradiol antibodies: structural characterisation and binding diversity.
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Highly specific anti-estradiol antibodies: structural characterisation and binding diversity.

机译：高度特异性的抗雌二醇抗体：结构表征和结合多样性。

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摘要

Subtle modulation of antibody-binding properties by protein engineering often lies with an accurate structural and energetic description of how an antigen is recognised. Thus, with the intent to increase the affinity and add a bias in favour of natural estradiol compared with its chemically modified immunogen, we have determined the crystal structure of two anti-estradiol monoclonal antibodies, 10G6D6 and 17E12E5. Although generated against the same estradiol derivative, these antibodies share little sequence identity, which is reflected in dissimilar binding pockets and in different positioning of the steroid. In both antibodies the characteristic 17-hydroxyl group is buried deeply at the bottom of hydrophobic pockets and stabilised by hydrogen bonds. Apart from this similarity, the steroid is oriented differently in the respective binding pockets. The high specificity of both antibodies has been mapped out, and even closely related steroids show low cross-reactivity. The structural studies of the complex formed between 10G6D6 and 6-CMO-estradiol have identified contacts between the 6-CMO coupling linker and an arginine residue from the heavy chain CDR2 segment. This segment is now being targeted by random mutagenesis to select mutants with a preference for natural estradiol compared to the branched hapten.
机译：通过蛋白质工程对抗体结合特性的微妙调节通常在于如何识别抗原的准确结构和能量描述。因此，与化学修饰的免疫原相比，为了增加亲和力并增加对天然雌二醇的偏爱，我们确定了两种抗雌二醇单克隆抗体10G6D6和17E12E5的晶体结构。尽管针对相同的雌二醇衍生物生成，但这些抗体几乎没有序列同一性，这反映在不同的结合口袋和类固醇的不同位置上。在这两种抗体中，特征性的17-羟基深深地埋在疏水性囊袋的底部，并通过氢键稳定。除了这种相似性之外，类固醇在各个结合口袋中的取向也不同。两种抗体都具有高特异性，甚至紧密相关的类固醇也显示出低交叉反应性。在10G6D6和6-CMO-雌二醇之间形成的复合物的结构研究确定了6-CMO偶联接头与重链CDR2片段中的精氨酸残基之间的接触。现在通过随机诱变靶向该片段，以选择与分支的半抗原相比优先选择天然雌二醇的突变体。

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