Structural mechanisms of assembling, activating and inhibiting CDK4

组装、激活和抑制CDK4的结构机制

• 批准号: G0900107/2
• 负责人: Jane Endicott
• 金额: $ 24.14万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0900107%2F2
• 关键词: Structural; mechanisms; assembling; activating; inhibiting

The growth and division of cells is strictly controlled at the molecular level by a series of enzymes that include the cyclin dependent protein kinases (CDKs). These enzymes are switched on and off in an orderly sequence, to ensure that cell division starts and stops at the required time. Though closely related in sequence, biological studies of the different members of the CDK family have revealed that each has unique properties. In particular, their activities can be regulated both by association with different families of regulatory proteins and by modification of the protein sequence by addition of a phosphate group to specific amino acid side chains. Our work, using the technique of X-ray crystallography, allows us to see the structures of these molecules at atomic resolution and so to learn how they differ from each other. The first aim of our work is to understand how members of the family of cyclin-dependent kinase inhibitors (CKIs) can bind to one member of the CDK family called CDK4 and either promote its assembly with its regulator cyclin D (resulting in an active enzyme complex) or inhibit its activity. CDK4 is also distinguished from other members of the CDK family in that it has a very limited number of substrates. The second aim of our work is to understand why this is the case. Aberrant CDK activity has been linked to cancer, neurological diseases, and rheumatoid arthritis. In particular, elevated levels of CDK4 activity, resulting from mutations in the genes for the proteins that regulate its activity, is commonly found in a number of cancers and is associated with a poor prognosis. In recent years, understanding a particular defect that leads to disease has led to exciting new medicines directed towards a particular target (e.g. the drugs Gleevec, Iressa and Herceptin for cancer treatment). A number of CDK-selective inhibitors are in clinical trials for the treatment of cancer. These agents all act by binding to the CDK active site to block CDK activity. Compounds that block other interactions made by CDK/cyclin complexes represent an alternative target for CDK-directed therapies. The work described in this project, to elaborate the interactions that mediate the binding of substrates to CDKs and CDK-regulatory proteins, will aid the further development of such compounds and may also reveal additional targets for inhibitor development.

细胞的生长和分裂在分子水平上受到包括细胞周期蛋白依赖性蛋白激酶（CDK）在内的一系列酶的严格控制。这些酶以有序的顺序打开和关闭，以确保细胞分裂在所需的时间开始和停止。虽然在序列上密切相关，但对CDK家族不同成员的生物学研究表明，每个成员都具有独特的特性。特别地，它们的活性可以通过与不同家族的调节蛋白的结合和通过向特定氨基酸侧链添加磷酸基团来修饰蛋白质序列来调节。我们的工作，使用X射线晶体学技术，使我们能够看到这些分子在原子分辨率的结构，从而了解它们彼此之间的差异。我们工作的第一个目的是了解细胞周期蛋白依赖性激酶抑制剂（CKIs）家族的成员如何与CDK家族的一个成员CDK 4结合，并促进其与其调节因子细胞周期蛋白D的组装（产生活性酶复合物）或抑制其活性。CDK 4与CDK家族其他成员的区别还在于它具有非常有限数量的底物。我们工作的第二个目的是理解为什么会这样。异常的CDK活性与癌症、神经系统疾病和类风湿性关节炎有关。特别是，由调节其活性的蛋白质的基因突变引起的CDK 4活性水平升高通常在许多癌症中发现，并且与预后不良相关。近年来，了解导致疾病的特定缺陷导致了针对特定靶点的令人兴奋的新药（例如用于癌症治疗的药物Gleevec，Iressa和Herceptin）。许多CDK选择性抑制剂正在进行治疗癌症的临床试验。这些试剂都通过结合CDK活性位点来阻断CDK活性。阻断由CDK/细胞周期蛋白复合物产生的其他相互作用的化合物代表了CDK定向疗法的替代靶标。本项目中描述的工作，阐述了介导底物与CDK和CDK调节蛋白结合的相互作用，将有助于进一步开发此类化合物，也可能揭示抑制剂开发的其他靶点。