CATALYTIC SUBUNIT OF CAMP DEPENDENT PROTEIN KINASE

营依赖蛋白激酶的催化亚基

• 批准号: 6119455
• 负责人: NGUYEN-HUU H XUONG
• 金额: --
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2000-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6119455
• 关键词: biomaterials; enzymes; proteins

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.

CAMP依赖的蛋白激酶(PKA)在 转运磷酸盐的细胞信号转导和功能 从三磷酸腺苷到底物。因为异常的激酶活性一直是 与癌症和其他疾病状态有关，有很大的努力来 设计各种激酶的特效、有效的抑制剂。PKA 由两个调节亚基和两个催化亚基(RC)组成 当结合第二信使cAMP时，两个RCS从 这个建筑群。RC在成员中高度保守(残基40-300) 属于蛋白激酶家族，作为较简单的成员之一，PKA 作为一个原型。已收集了RC的三个数据集，地址为 7-1和9-1：1)酶RC-峰II(APO2)上的SSRL 它有三个磷酸化位点-3E。2)辅酶RC-峰 III(Apo3)，有两个磷酸化位点-2.6E。3)巴拉诺 模拟绑定到RC(BD2)-2.1E。脱辅酶结构为 对于理解 配位和非配位RC形式及用于研究结构域运动 配基结合所必需的。BD2的结构揭示了RC如何 与天然产物抑制剂(IC50)类似物的络合物 0.015微米)。这三种结构将为配体提供进一步的洞察力 RC的结合和有关活性部位残基的细节 参与配基识别将有助于设计更多 用于治疗用途的有效的和选择性的PKA抑制剂。