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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Binding of small molecules to an adaptive protein-protein interface.
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Binding of small molecules to an adaptive protein-protein interface.

机译：小分子与适应性蛋白质-蛋白质界面的结合。

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摘要

Understanding binding properties at protein-protein interfaces has been limited to structural and mutational analyses of natural binding partners or small peptides identified by phage display. Here, we present a high-resolution analysis of a nonpeptidyl small molecule, previously discovered by medicinal chemistry [Tilley, J. W., et al. (1997) J. Am. Chem. Soc. 119, 7589-7590], which binds to the cytokine IL-2. The small molecule binds to the same site that binds the IL-2 alpha receptor and buries into a groove not seen in the free structure of IL-2. Comparison of the bound and several free structures shows this site to be composed of two subsites: one is rigid, and the other is highly adaptive. Thermodynamic data suggest the energy barriers between these conformations are low. The subsites were dissected by using a site-directed screening method called tethering, in which small fragments were captured by disulfide interchange with cysteines introduced into IL-2 around these subsites. X-ray structures with the tethered fragments show that the subsite-binding interactions are similar to those observed with the original small molecule. Moreover, the adaptive subsite tethered many more compounds than did the rigid one. Thus, the adaptive nature of a protein-protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface.
机译：理解蛋白质-蛋白质界面的结合特性仅限于通过噬菌体展示鉴定的天然结合伴侣或小肽的结构和突变分析。在这里，我们提出了一种非肽基小分子的高分辨率分析方法，该方法以前是通过药物化学发现的[Tilley，J. W.，et al。 （1997）J. Am。化学Soc。 119，7589-7590]，其与细胞因子IL-2结合。小分子与结合IL-2α受体的相同位点结合，并埋入在IL-2的自由结构中看不到的凹槽中。对有界结构和几个自由结构的比较表明，该位点由两个子位点组成：一个是刚性位点，另一个是高度适应性的位点。热力学数据表明这些构象之间的能垒很低。通过使用称为系链的定点筛选方法对亚位点进行解剖，其中通过与这些亚位点周围引入IL-2的半胱氨酸的二硫键交换捕获小片段。带有束缚片段的X射线结构表明，亚位点结合相互作用与原始小分子观察到的相似。此外，自适应子站点比刚性子站点束缚了更多的化合物。因此，蛋白质-蛋白质界面的适应性为小分子结合提供了位点，并强调了应用基于结构的设计策略所面临的挑战，该策略无法准确预测动态蛋白质表面。

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