靶向粘着斑激酶（FAK）与胰岛素样生长因子-1受体（IGF-1R）之间的蛋白质相互作用位点。
Targeting of the protein interaction site between FAK and IGF-1R.
作者信息
Zheng Donghang, Kurenova Elena, Ucar Deniz, Golubovskaya Vita, Magis Andrew, Ostrov David, Cance William G, Hochwald Steven N
机构信息
Department of Surgery, University of Florida, Gainesville, FL, USA.
出版信息
Biochem Biophys Res Commun. 2009 Oct 16;388(2):301-5. doi: 10.1016/j.bbrc.2009.07.156. Epub 2009 Aug 5.
Abstract
The interaction of focal adhesion kinase (FAK) and insulin-like growth factor-1 receptor (IGF-1R) plays an important role in cancer cell survival. Targeting this interaction with small molecule drugs could be a novel strategy in cancer therapy. By a series of pull-down assays using GST-tagged FAK fragments and His-tagged IGF-1R intracellular fragments, we showed that the FAK-NT2 (a.a. 127-243) domain directly interacts with the N-terminal part of the IGF-1R intracellular domain. Overexpressed FAK-NT2 domain was also shown to co-localize with IGF-1R in pancreatic cells. Computational modeling was used to predict the binding configuration of these two domains and to screen for small molecules binding to the interaction site. This strategy successfully identified a lead compound that disrupts FAK/IGF-1R interaction.
摘要
粘着斑激酶（FAK）与胰岛素样生长因子-1受体（IGF-1R）的相互作用在癌细胞存活中起重要作用。用小分子药物靶向这种相互作用可能是癌症治疗中的一种新策略。通过一系列使用谷胱甘肽S-转移酶（GST）标记的FAK片段和组氨酸（His）标记的IGF-1R细胞内片段的下拉实验，我们表明FAK-NT2（氨基酸127-243）结构域直接与IGF-1R细胞内结构域的N端部分相互作用。过表达的FAK-NT2结构域也显示在胰腺细胞中与IGF-1R共定位。使用计算模型预测这两个结构域的结合构型，并筛选与相互作用位点结合的小分子。该策略成功鉴定出一种破坏FAK/IGF-1R相互作用的先导化合物。
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