Probing the druggability of protein-protein interactions: targeting the Notch1 receptor ankyrin domain using a fragment-based approach
Probing the druggability of protein-protein interactions: targeting the Notch1 receptor ankyrin domain using a fragment-based approach
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DOI：
10.1042/bst0391327
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发表时间：
2011-10-01
影响因子：
3.9
通讯作者：
Blundell, Tom L.
中科院分区：
文献类型：
--
作者：
Abdel-Rahman, Noha;Martinez-Arias, Alfonso;Blundell, Tom L.
为了在药物发现中实现更大的选择性，学术界和工业界的研究人员都将目标对准了细胞调控系统。这通常涉及到以调节多蛋白组装的蛋白质-蛋白质相互作用为目标。蛋白质-蛋白质界面被广泛认为是具有挑战性的靶点，因为它们往往较大且相对平坦，因此通常没有所谓的“可药物基因组”所特有的凹形结合部位。一个这样的原型核蛋白靶标是Notch转录复合体，其中一个广泛的蛋白质-蛋白质相互作用网络稳定了由ankyrin结构域、CSL(CBF1/无毛/LAG-1的抑制子)和MAML(主脑样蛋白)组成的三元复合体。Notch活性增强与T-ALL(T细胞急性淋巴细胞性白血病)的发生有关，Notch的选择性抑制剂将成为有用的抗癌药物。在本文中，我们描述了一种基于片段的方法来探索锚蛋白结构域的可药性。利用生物物理方法和X射线晶体结构分析，我们证明了分子可以结合到CSL和MAML界面区域的锚定结构域表面。我们表明，它们可能代表着设计更大化合物的起点，这些化合物可以抑制重要的蛋白质-蛋白质相互作用，从而稳定Notch复合体。考虑到锚蛋白结构域的相对平淡无奇的拓扑结构，这一意想不到的发展应该会鼓励其他人使用基于片段的方法来探索这种具有挑战性的非多蛋白系统的可药性。
In order to achieve greater selectivity in drug discovery, researchers in both academia and industry are targeting cell regulatory systems. This often involves targeting the protein-protein interactions of regulatory multiprotein assemblies. Protein-protein interfaces are widely recognized to be challenging targets as they tend to be large and relatively flat, and therefore usually do not have the concave binding sites that characterize the so-called 'druggable genome'. One such prototypic nnultiprotein target is the Notch transcription complex, where an extensive network of protein-protein interactions stabilize the ternary complex comprising the ankyrin domain, CSL (CBF1/suppressor of Hairless/Lag-1) and MAML (Mastermind-like). Enhanced Notch activity is implicated in the development of T-ALL (T-cell acute lymphoblastic leukaemia) and selective inhibitors of Notch would be useful cancer medicines. In the present paper, we describe a fragment-based approach to explore the druggability of the ankyrin domain. Using biophysical methods and X-ray crystal structure analyses, we demonstrate that molecules can bind to the surface of the ankyrin domain at the interface region with CSL and MAML. We show that they probably represent starting points for designing larger compounds that can inhibit important protein-protein interactions that stabilize the Notch complex. Given the relatively featureless topography of the ankyrin domain, this unexpected development should encourage others to explore the druggability of such challenging nnultiprotein systems using fragment-based approaches.