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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞外信号调节蛋白ERK2是细胞增殖的重要调节因子，与多种癌症密切相关。由于不同激酶的ATP结合区的相似性以及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定的ERK2活性抑制剂，破坏其与蛋白质底物(如c-Myc、c-Fos、RSK-1和ELK-1)的相互作用，从而以特定的、不依赖于ATP的方式发挥作用。蛋白质-抑制剂复合体的晶体结构将被用来理解小配体干扰细胞信号传递的机制，并将利用关于特定相互作用的信息来合理设计改进的抑制剂。 我们已经成功地将ERK2与几种通过基于结构的药物设计和功能分析相结合的抑制剂进行了共结晶。晶体很小，使用同步辐射可以获得分辨率为2？或更高的数据。这大大提高了揭示蛋白质-配体相互作用的细节水平。由于该项目的性质，必须对大量晶体进行筛选，从而进一步需要获得同步辐射光源。

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.