CATALYTIC SUBUNIT OF CAMP DEPENDENT PROTEIN KINASE

cAMP依赖性蛋白激酶（PKA）在细胞内的信号转导中起重要作用。 细胞信号转导和功能通过转移磷酸盐 从ATP到其底物。 由于异常的激酶活性已经 与癌症和其他疾病状态有关，有很大的努力， 设计各种激酶的特异性强效抑制剂。 PKA 由两个调节亚基和两个催化亚基（rC）组成 在结合第二信使cAMP后，两个rCs从 复杂的。 rC在成员间高度保守（残基40-300） PKA是蛋白激酶家族中最简单的成员之一， 作为原型。 已收集了三组rC数据， 光束线7-1和9-1上的SSRL：1）脱辅基酶rC -峰II（apo 2） 它有三个磷酸化位点3E。 2)脱辅基酶rC峰 III（apo 3）有两个磷酸化位点2.6E。 3)巴拉诺尔 与rC（BD 2）- 2.1 E结合的类似物。 脱辅基酶的结构是 重要的是要了解之间的结构差异， 配体和非配体rC形式，并用于研究结构域运动 配体结合所必需的。 BD 2的结构揭示了rC 与天然产物抑制剂类似物的复合物（IC 50 0.015uM）。 这三种结构将为配体的进一步研究提供参考。 通过rC结合和关于活性位点残基的细节 参与配体识别将有助于设计更多的 用于治疗用途的PKA的有效和选择性抑制剂。

The cAMP-dependent protein kinase (PKA) plays an important role in cellular signal transduction and functions by transferring a phosphate from ATP to its substrate. Since aberrant kinase activity has been linked to cancer and other disease states, there are great efforts to design specific, potent inhibitors of the various kinases. PKA consists of two regulatory subunits and two catalytic subunits (rC) and upon binding the second messenger, cAMP, two rCs dissociate from the complex. rC is highly conserved (residues 40-300) among members of the protein kinase family, and as one of the simpler members, PKA serves as a prototype. Three data sets for rC have been collected at SSRL on beam lines 7-1 and 9-1: 1) apoenzyme rC - peak II (apo2) which has three phosphorylation sites - 3 E . 2) apoenzyme rC - peak III (apo3) which has two phosphorylation sites - 2.6 E . 3) balanol analog bound to rC (BD2) - 2.1 E . The apoenzyme structures are important for understanding the structural differences between the liganded and the unliganded rC forms and for studying domain movements necessary for ligand binding. The structure of BD2 reveals how rC complexes with an analog of a natural product inhibitor (IC50 0.015uM). The three structures will provide further insight to ligand binding by rC and the details regarding the active site residues involved in ligand recognition will facilitate the design of more potent and selective inhibitors of PKA for therapeutic use.