One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1β
One Target-Two Different Binding Modes: Structural Insights into Gevokizumab and Canakinumab Interactions to Interleukin-1β
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DOI：
10.1016/j.jmb.2012.09.021
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发表时间：
2013-01-09
影响因子：
5.6
通讯作者：
Nar, Herbert
中科院分区：
文献类型：
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作者：
Blech, Michaela;Peter, Daniel;Nar, Herbert
白介素 1 β (IL-1 β) 是炎症和多种免疫反应的关键协调者。 IL-1β 通过 I 型白细胞介素 1 受体 (IL-1RI) 和白细胞介素 1 受体辅助蛋白 (IL-1RAcP) 发挥作用，它们共同形成异源三聚体信号传导复合物。 Canakinumab 和 gevokizumab 是高度特异性的 IL-1 β 单克隆抗体。已知卡那奴单抗通过竞争与 IL-1R 的结合来中和 IL-1 β，从而阻断抗原：抗体复合物的信号传导。 Gevokizumab 据称是一种调节性治疗抗体，通过降低 IL-1R1:IL-1RAcP 信号复合物的亲和力来调节 IL-1 β 生物活性。卡那单抗和吉沃克珠单抗如何影响 IL-1 β 信号传导尚未通过实验确定。我们分析了 canakinumab 和 gevokizumab 抗体结合片段 (Fab) 及其与 IL-1 beta 的二元复合物的晶体结构。此外，我们通过 NMR 表位作图研究对抗体所采用的 IL-1 β 上的表位进行了表征。 NMR 和 X 射线数据的直接比较表明，由晶体结构定义的表位主要包含那些其 NMR 共振在复合物形成时受到严重干扰的残基。抗原:Fab 共结构证实了先前确定的 IL-1 β 上的关键接触残基，并提供了对导致其对 IL-1 β 信号传导的独特调节的机制的深入了解。 IL-1R 和卡那单抗在 IL-1β 上的结合界面的显着空间重叠导致 IL-1β 与其受体结合的竞争性抑制。相比之下，gevokizumab 占据 IL-1 β 上的变构位点，并且复合物形成导致与 IL-1RI 的结合亲和力轻微降低。这表明 IL-1 β 途径减弱有两种不同的机制。 (C) 2012 Elsevier Ltd. 保留所有权利..
Interleukin-1 beta (IL-1 beta) is a key orchestrator in inflammatory and several immune responses. IL-1 beta exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1 beta monoclonal antibodies. Canakinumab is known to neutralize IL-1 beta by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1 beta bioactivity by reducing the affinity for its IL-1R1:IL-1RAcP signaling complex. How IL-1 beta signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1 beta. Furthermore, we characterized the epitopes on IL-1 beta employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1 beta and provide insight into the mechanisms leading to their distinct modulation of IL-1 beta signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1 beta causes competitive inhibition of the association of IL-1 beta and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1 beta and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1 beta pathway attenuation. (C) 2012 Elsevier Ltd. All rights reserved..