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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 细胞外信号调节激酶ERK 2是细胞增殖的重要介质，并与许多癌症有关。由于不同激酶的ATP结合区域的相似性和ERK 2在正常细胞功能中的重要性，直接抑制其激酶活性存在问题。本项目的目标是开发特异性ERK 2活性抑制剂，其破坏ERK 2与蛋白质底物（例如c-Myc，c-Fos，RSK-1和ELK-1）的相互作用，从而以特异性和ATP非依赖性方式发挥作用。蛋白质-抑制剂复合物的晶体结构将用于理解小配体干扰细胞信号传导的机制，并将导致使用有关特定相互作用的信息来合理设计改进的抑制剂。 我们已经成功地共结晶ERK 2与几种抑制剂，确定了基于结构的药物设计和功能测定相结合。晶体很小，使用同步辐射可以获得2 º分辨率或更高的数据。这大大提高了蛋白质-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，进一步需要获得同步辐射源。

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.