Protein painting reveals solvent-excluded drug targets hidden within native protein-protein interfaces.
Protein painting reveals solvent-excluded drug targets hidden within native protein-protein interfaces.
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DOI：
10.1038/ncomms5413
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发表时间：
2014-07-22
影响因子：
16.6
通讯作者：
Liotta, Lance A.
中科院分区：
文献类型：
--
作者：
Luchini, Alessandra;Espina, Virginia;Liotta, Lance A.
识别蛋白质及其结合伴侣之间的接触区域对于创建阻断相互作用的疗法至关重要。不幸的是，这种接触区域非常难以表征，因为它们隐藏在结合界面内。在这里，我们介绍了蛋白质绘画作为一种新的工具，采用小分子作为分子涂料，紧紧地覆盖蛋白质-蛋白质复合物的表面。阻断胰蛋白酶切割位点的分子涂料被排除在结合界面之外。在质谱分析之后，只有隐藏在界面中的肽作为阳性命中出现，揭示了作为药物靶标的功能接触区域。我们利用蛋白质涂绘技术发现了IL 1 β配体、受体IL 1 RI和辅助蛋白IL 1 RAcP之间的三向相互作用区域。然后，我们使用这些信息来创建阻断相互作用并消除IL 1 β细胞信号传导的肽和单克隆抗体。该技术广泛适用于发现蛋白质相互作用的药物靶点。 确定蛋白质与另一分子结合的位点是设计旨在防止这种相互作用的治疗剂的重要因素。在这里，作者用表面结合分子包裹蛋白质受体复合物，并使用质谱法确定它们的相互作用区域。
Identifying the contact regions between a protein and its binding partners is essential for creating therapies that block the interaction. Unfortunately, such contact regions are extremely difficult to characterize because they are hidden inside the binding interface. Here we introduce protein painting as a new tool that employs small molecules as molecular paints to tightly coat the surface of protein–protein complexes. The molecular paints, which block trypsin cleavage sites, are excluded from the binding interface. Following mass spectrometry, only peptides hidden in the interface emerge as positive hits, revealing the functional contact regions that are drug targets. We use protein painting to discover contact regions between the three-way interaction of IL1β ligand, the receptor IL1RI and the accessory protein IL1RAcP. We then use this information to create peptides and monoclonal antibodies that block the interaction and abolish IL1β cell signalling. The technology is broadly applicable to discover protein interaction drug targets. Identifying the site where a protein binds to another molecule is an important factor for the design of therapeutics intended to prevent this interaction. Here, the authors coat protein–receptor complexes with surface-binding molecules, and determine their interacting regions using mass spectrometry.
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影响因子：
3
作者：
Flores SC;Gerstein MB
通讯作者：
Gerstein MB
DOI：
10.1111/j.1432-1033.1974.tb03309.x
发表时间：
1974-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
CLEGG, C;HAYES, D
通讯作者：
HAYES, D
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.6
作者：
Blech, Michaela;Peter, Daniel;Nar, Herbert
通讯作者：
Nar, Herbert
影响因子：
14.9
作者：
Kim, DE;Chivian, D;Baker, D
通讯作者：
Baker, D