STUDIES OF INHIBITION OF MITOGEN ACTIVATED PROTEIN KINASE 1 (ERK2)

丝裂原激活蛋白激酶 1 (ERK2) 抑制的研究

• 批准号: 8170295
• 负责人: EDVIN V POZHARSKIY
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170295
• 关键词: Binding; Biological Assay; Cell Proliferation; Cell physiology; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Drug Design; ELK1 gene; Extracellular Signal Regulated Kinases; FOS gene; Funding; Goals; Grant; Institution; Lead; Ligands; MAPK1 gene; Malignant Neoplasms; Mediator of activation protein; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Nature; Normal Cell; Phosphotransferases; Proteins; Research; Research Personnel; Resolution; Resources; Signal Transduction; Source; Structure; United States National Institutes of Health; base; c-myc Genes; design; improved; inhibitor/antagonist; protein structure; synchrotron radiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The extracellular signal regulated kinase ERK2 is an important mediator of cell proliferation and has been implicated in a number of cancers. Inhibiting its kinase activity directly is problematic due to similarities of ATP-binding regions of different kinases and importance of ERK2 in normal cell functioning. The goal of this project is to develop specific ERK2 activity inhibitors which disrupt its interaction with protein substrates (e.g. c-Myc, c-Fos, RSK-1, and ELK-1) and thus act in specific and ATP-independent manner. Crystal structures of protein-inhibitor complexes will be used to understand the mechanisms by which small ligands interfere with cell signaling and will lead to rational design of improved inhibitors using the information about specific interactions. We have successfully co-crystallized ERK2 with several inhibitors identified by combination of structure-based drug design and functional assays. Crystals are small and use of synchrotron radiation allows to obtain data at 2¿ resolution and higher. This greatly enhances the level of detail at which the protein-ligand interactions are revealed. Due to the nature of the project, large numbers of crystals have to be screened, further necessitating the access to synchrotron radiation source.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 细胞外信号调节激酶 ERK2 是细胞增殖的重要介质，与多种癌症有关。由于不同激酶 ATP 结合区域的相似性以及 ERK2 在正常细胞功能中的重要性，直接抑制其激酶活性是有问题的。该项目的目标是开发特异性 ERK2 活性抑制剂，破坏其与蛋白质底物（例如 c-Myc、c-Fos、RSK-1 和 ELK-1）的相互作用，从而以特异性且不依赖于 ATP 的方式发挥作用。蛋白质-抑制剂复合物的晶体结构将用于了解小配体干扰细胞信号传导的机制，并将利用有关特定相互作用的信息合理设计改进的抑制剂。 我们通过基于结构的药物设计和功能测定相结合，成功地将 ERK2 与几种抑制剂共结晶。晶体很小，使用同步加速器辐射可以获得 2¿ 分辨率及更高的数据。这极大地提高了揭示蛋白质-配体相互作用的细节水平。由于该项目的性质，必须筛选大量晶体，进一步需要使用同步加速器辐射源。