MOLECULAR MECHANISM OF ACTIVATION OF A NOVEL INTRACELLULAR CAMP RECEPTOR

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 CAMP介导的信号在生理条件和疾病状态下调节无数重要的生物学过程，包括糖尿病、心力衰竭和癌症。在真核细胞中，cAMP的作用是由两种普遍表达的cAMP受体介导的，一种是经典的蛋白激酶A/cAMP依赖的蛋白激酶(PKA/CAPK)，另一种是新近发现的由cAMP/cAMP调节的鸟核苷酸交换因子(EPAC/cAMP-gef)直接激活的交换蛋白。两个普遍表达的cAMP效应器的存在为在空间和时间上更精确和完整地控制cAMP信号通路提供了一种机制。这项建议的目的是通过使用X射线结晶学解决全长Epac2-cAMP络合物的晶体结构来填补我们目前知识中的空白。更好地了解cAMP介导的信号转导可能会导致识别新的药物靶点和开发新的或改进的治疗药物。

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. cAMP-mediated signaling regulates a myriad of important biological processes under physiological conditions and disease states, including diabetes, heart failure and cancer. In eukaryotic cells, the effects of cAMP are mediated by two ubiquitously expressed intracellular cAMP receptors, the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK) and the recently discovered exchange protein directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (Epac/cAMP-GEF). The existence of two ubiquitously expressed cAMP effectors provides a mechanism for a more precise and integrated control of the cAMP signaling pathways in a spatial and temporal manner. The objective of this proposal is to fill the gap in our current knowledge by solving the crystal structure of full length Epac2-cAMP complex using X-ray crystallography. A better understanding of cAMP-mediated signal transduction could potentially lead to the identification of novel drug targets and the development of new or improved therapeutic agents.