文章：

抑制瞬时蛋白相互作用：来自Cdc25蛋白酪氨酸磷酸酶的经验教训

Inhibiting transient protein–protein interactions: lessons from the Cdc25 protein tyrosine phosphatases

原文发布日期：2007-02-08

DOI: 10.1038/nrc2087

类型: Review Article

开放获取: 否

要点：

1. The eukaryotic cell cycle is controlled by the activity of many protein kinases and phosphatases. For example, the cell division cycle 25 (Cdc25) phosphatases dephosphorylate and thereby activate the cyclin-dependent kinase (CDK)–cyclin complexes.
2. Cdc25 phosphatases serve as potential targets for anticancer development because of their role in promoting cell-cycle progression and their frequent overexpression in various cancers.
3. The interactions of protein kinases and protein phosphatases with their protein substrates are transient, and are therefore poorly characterized and problematic for drug discovery.
4. A docking site remote from the active site in Cdc25 mediates efficient recognition of phosphorylated CDK–cyclins.
5. In a computationally derived and experimentally validated model of the docking orientation of CDC25B with its CDK–cyclin substrate, the interfacial contacts in the remote docking site are primarily ionic.
6. The remote docking site is as important to the in vivo function of CDC25B as the catalytic residues in the active site.
7. A pocket exists adjacent to the docking site on CDC25B to which potential inhibitors of this transient protein–protein interaction should be targeted.
8. Although deciphering the details of transient protein–protein interactions involved in cell-cycle control is difficult, a systematic and thorough approach can set the framework for the discovery and development of inhibitors that can serve as cancer therapeutics.

要点翻译：

1. 真核细胞的细胞周期受到多种蛋白激酶和磷酸酶活性的调控。例如，细胞分裂周期25（Cdc25）磷酸酶通过去磷酸化作用激活细胞周期蛋白依赖性激酶（CDK）-细胞周期蛋白复合物。
2. Cdc25磷酸酶因在促进细胞周期进程中发挥作用，并在多种癌症中频繁过表达，因而成为抗癌药物开发的潜在靶点。
3. 蛋白激酶和蛋白磷酸酶与其蛋白底物间的相互作用具有瞬时性，难以表征，这为药物发现带来了挑战。
4. Cdc25中一个远离活性位点的对接位点介导了对磷酸化CDK-细胞周期蛋白的高效识别。
5. 通过计算模拟和实验验证的CDC25B与其CDK-细胞周期蛋白底物的对接取向模型显示，远端对接位点的界面接触主要为离子相互作用。
6. 该远端对接位点对CDC25B的体内功能的重要性，不亚于活性位点中的催化残基。
7. CDC25B对接位点附近存在一个口袋结构，针对该瞬时蛋白-蛋白相互作用的潜在抑制剂应靶向此区域。
8. 尽管解析细胞周期调控中瞬时蛋白-蛋白相互作用的细节存在困难，但系统而深入的研究方法能为发现和开发作为癌症治疗剂的抑制剂奠定框架。

英文摘要：

Transient protein–protein interactions have key regulatory functions in many of the cellular processes that are implicated in cancerous growth, particularly the cell cycle. Targeting these transient interactions as therapeutic targets for anticancer drug development seems like a good idea, but it is not a trivial task. This Review discusses the issues and difficulties that are encountered when considering these transient interactions as drug targets, using the example of the cell division cycle 25 (Cdc25) phosphatases and their cyclin-dependent kinase (CDK)–cyclin protein substrates.

摘要翻译： 

短暂性蛋白-蛋白相互作用在细胞周期等许多与癌症生长相关的细胞过程中具有关键的调控功能。将这些短暂相互作用作为抗癌药物开发的靶点似乎是一个好主意，但绝非易事。本综述以细胞分裂周期25（Cdc25）磷酸酶及其细胞周期蛋白依赖性激酶（CDK）-细胞周期蛋白底物为例，探讨了将这些短暂相互作用视为药物靶点时所面临的问题和困难。

原文链接：

Inhibiting transient protein–protein interactions: lessons from the Cdc25 protein tyrosine phosphatases