X-RAY CRYSTALLOGRAPHIC STUDIES OF RIBOSOMAL S6 KINASE 2 (RSK2)

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心赠款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 p90 kDa核糖体S6激酶2（RSK 2）属于促分裂原活化蛋白激酶信号通路，调节多种细胞过程，如细胞生长和分化，以及细胞存活和增殖。RSK 2在人前列腺癌、乳腺癌、肺癌、结肠癌和皮肤癌中过表达。RSK 2与骨肉瘤的发展相关，RSK 2的敲低有效地诱导人骨髓瘤细胞的凋亡。RSK 2是独特的双激酶，其特征在于在一个多肽中存在两个不同的功能激酶结构域。迄今为止，全长RSK 2的三维结构尚未确定，其激活的精确机制仍然难以捉摸。缺乏这些知识阻碍了治疗癌症所需的选择性抑制剂的开发。该项目的重点是解析全长RSK 2和/或其单独激酶结构域的晶体结构。我们的目标是使用晶体学方法来定义两个激酶结构域之间的结构-功能关系。假设RSK 2的N-末端激酶结构域采用独特的激酶构象。 细胞外信号调节激酶2（ERK 2）是RSK 2的上游活化激酶，其结合至RSK 2的C末端并使其磷酸化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The p90 kDa ribosomal S6 kinase 2 (RSK2) belongs to the mitogen-activated protein kinase signaling pathway and regulates diverse cellular processes such as cell growth and differentiation, as well as cell survival and proliferation. RSK2 is overexpressed in human prostate cancer, breast cancer, lung, colon and skin cancer. RSK2 is associated with osteosarcoma development, and knockdown of RSK2 effectively induces apoptosis in human myeloma cells. RSK2 is unique dual kinase, which is characterized by the presence of two distinct functional kinase domains in one polypeptide. The three-dimensional structures of full length RSK2 has not been determined to date, and the precise mechanisms of its activation remain elusive. Lack of such knowledge impedes development of their selective inhibitors needed for treatment of cancers. The focus of the project is to resolve crystals structure of full length RSK2 and/or its separate kinase domains. The objective is to define structure-function relationship between the two kinase domains using a crystallographic approach. The hypothesis is that the N-terminal kinase domain of RSK2 adopts a unique kinase conformation. The extracellular signal- regulated kinase 2 (ERK2) is up-stream activating kinase of RSK2, that binds to the C-terminal RSK2 and phosphorylates it.