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首页> 外文期刊>Biochemistry >Inhibiting protein-protein interactions: a model for antagonist design.
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Inhibiting protein-protein interactions: a model for antagonist design.

机译：抑制蛋白质间相互作用：拮抗剂设计模型。

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摘要

Protein-protein interactions (PPI) are a ubiquitous mode of transmitting signals in cells and tissues. We are testing a stepwise, generic, structure-driven approach for finding low molecular weight inhibitors of protein-protein interactions. The approach requires development of a high-affinity, single chain antibody directed specifically against the interaction surface of one of the proteins to obtain structural information on the interface. To this end, we developed a single chain antibody (sc1E3) against hIL-1beta that exhibited the equivalent affinity of the soluble IL-1 receptor type I (sIL-1R) for hIL-1beta and competitively blocked the sIL-1R from binding to the cytokine. The antibody proved to be more specific for hIL-1beta than the sIL-1R in that it failed to bind to either murine IL-1beta or human/murine IL-1alpha proteins. Additionally, failure of sc1E3 to bind to several hIL-1beta mutant proteins, altered at receptor site B, indicated that the antibody interacted preferentially with this site. This, coupled with other surface plasmon resonance and isothermal titration calorimetry measurements, shows that sc1E3 can achieve comparable affinity of binding hIL-1beta as the receptor through interactions at a smaller interface. This stable single chain antibody based heterodimer has simplified the complexity of the IL-1/IL-1R PPI system and will facilitate the design of the low molecular weight inhibitors of this interaction.
机译：蛋白质-蛋白质相互作用（PPI）是在细胞和组织中传输信号的普遍方式。我们正在测试一种逐步的，通用的，结构驱动的方法，以发现蛋白质相互作用的低分子量抑制剂。该方法需要开发一种高亲和力的单链抗体，专门针对一种蛋白质的相互作用表面，以获得界面上的结构信息。为此，我们开发了针对hIL-1beta的单链抗体（sc1E3），该抗体表现出可溶性I-1型I类受体（sIL-1R）对hIL-1beta的等效亲和力，并竞争性地阻断sIL-1R与细胞因子。事实证明，该抗体对hIL-1beta的特异性高于sIL-1R，因为它无法与鼠类IL-1beta或人/鼠IL-1alpha蛋白结合。此外，sc1E3未能结合到几个在受体位点B处改变的hIL-1beta突变蛋白，表明该抗体优先与该位点相互作用。这与其他表面等离振子共振和等温滴定量热法测量相结合，表明sc1E3可通过较小界面处的相互作用获得与hIL-1beta作为受体的可比亲和力。这种稳定的基于单链抗体的异二聚体简化了IL-1 / IL-1R PPI系统的复杂性，并将有助于设计这种相互作用的低分子量抑制剂。

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