Structural basis of CX-4945 binding to human protein kinase CK2
Structural basis of CX-4945 binding to human protein kinase CK2
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DOI：
10.1016/j.febslet.2010.11.019
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发表时间：
2011-01-03
期刊：
影响因子：
3.5
通讯作者：
Le, Hung V.
中科院分区：
文献类型：
--
作者：
Ferguson, Andrew D.;Sheth, Payal R.;Le, Hung V.
蛋白激酶CK2 （CK2）是一种组成活性的丝氨酸/苏氨酸激酶，参与维持细胞稳态的多种重要作用。CK2表达水平升高导致调节转录的关键信号通路失调，并与癌症有关。据报道，腺苷-5'-三磷酸竞争性抑制剂CX-4945在多种癌细胞系中显示出广谱的抗增殖活性。虽然CX-4945酶的IC50已被报道，但其与CK2 α结合的热力学和结构基础仍不清楚。这里展示的是人类CK2 α与CX-4945和磷酸腺苷酸配合物在2.7和1.3埃下的晶体结构。本文还描述了CX-4945结合的生物物理分析。这一数据为设计针对这一新兴癌症靶点的更有效抑制剂提供了结构上的基本原理。(C) 2010年欧洲生化学会联合会。Elsevier b.v.版权所有。
Protein kinase CK2 (CK2), a constitutively active serine/threonine kinase, is involved in a variety of roles essential to the maintenance of cellular homeostasis. Elevated levels of CK2 expression results in the dysregulation of key signaling pathways that regulate transcription, and has been implicated in cancer. The adenosine-5'-triphosphate-competitive inhibitor CX-4945 has been reported to show broad spectrum anti-proliferative activity in multiple cancer cell lines. Although the enzymatic IC50 of CX-4945 has been reported, the thermodynamics and structural basis of binding to CK2 alpha remained elusive. Presented here are the crystal structures of human CK2 alpha in complex with CX-4945 and adenylyl phosphoramidate at 2.7 and 1.3 angstrom, respectively. Biophysical analysis of CX-4945 binding is also described. This data provides the structural rationale for the design of more potent inhibitors against this emerging cancer target. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.