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首页> 外文期刊>Journal of Molecular Biology >Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab.
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Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab.

机译：Ustekinumab对IL-12和IL-23双重识别的结构基础。

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摘要

Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that share a common p40 subunit, paired with p35 and p19 subunits, respectively. They represent an attractive class of therapeutic targets for the treatment of psoriasis and other immune-mediated diseases. Ustekinumab is a fully human monoclonal antibody (mAb) that binds specifically to IL-12/IL-23p40 and neutralizes human IL-12 and IL-23 bioactivity. The crystal structure of ustekinumab Fab (antigen binding fragment of mAb), in complex with human IL-12, has been determined by X-ray crystallography at 3.0 A resolution. Ustekinumab Fab binds the D1 domain of the p40 subunit in a 1:1 ratio in the crystal, consistent with a 2 cytokines:1 mAb stoichiometry, as measured by isothermal titration calorimetry. The structure indicates that ustekinumab binds to the same epitope on p40 in both IL-12 and IL-23 with identical interactions. Mutational analyses confirm that several residues identified in the IL-12/IL-23p40 epitope provide important molecular binding interactions with ustekinumab. The electrostatic complementarity between the mAb antigen binding site and the p40 D1 domain epitope appears to play a key role in antibody/antigen recognition specificity. Interestingly, this structure also reveals significant structural differences in the p35 subunit and p35/p40 interface, compared with the published crystal structure of human IL-12, suggesting unusual and potentially functionally relevant structural flexibility of p35, as well as p40/p35 recognition. Collectively, these data describe unique observations about IL-12p35 and ustekinumab interactions with p40 that account for its dual binding and neutralization of IL-12 and IL-23.
机译：白介素（IL）-12和IL-23是异二聚体促炎细胞因子，共有一个共同的p40亚基，分别与p35和p19亚基配对。它们代表了用于治疗牛皮癣和其他免疫介导疾病的有吸引力的一类治疗靶标。 Ustekinumab是完全人单克隆抗体（mAb），可特异性结合IL-12 / IL-23p40，并中和人IL-12和IL-23的生物活性。 ustekinumab Fab（mAb的抗原结合片段）与人IL-12的晶体结构已通过X射线晶体学以3.0 A的分辨率进行了测定。 Ustekinumab Fab在晶体中以1：1的比例结合p40亚基的D1结构域，这与2种细胞因子：1 mAb的化学计量一致，如通过等温滴定量热法所测。该结构表明，ustekinumab在IL-12和IL-23中以相同的相互作用与p40上的相同表位结合。突变分析证实，在IL-12 / IL-23p40表位中鉴定出的几个残基提供了与ustekinumab重要的分子结合相互作用。 mAb抗原结合位点与p40 D1结构域表位之间的静电互补似乎在抗体/抗原识别特异性中起关键作用。有趣的是，与人IL-12公布的晶体结构相比，该结构还揭示了p35亚基和p35 / p40界面的显着结构差异，表明p35具有非同寻常的和潜在的功能相关的结构灵活性，以及​​p40 / p35的识别能力。总的来说，这些数据描述了关于IL-12p35和ustekinumab与p40相互作用的独特观察结果，这说明了其对IL-12和IL-23的双重结合和中和作用。

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