Drug Design Department, Merck Research Laboratory, Kenilworth, NJ 07033, USA.
FEBS Lett. 2011 Jan 3;585(1):104-10. doi: 10.1016/j.febslet.2010.11.019. Epub 2010 Nov 18.
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 IC(50) of CX-4945 has been reported, the thermodynamics and structural basis of binding to CK2α remained elusive. Presented here are the crystal structures of human CK2α in complex with CX-4945 and adenylyl phosphoramidate at 2.7 and 1.3 Å, 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.
蛋白激酶 CK2（CK2）是一种组成性激活的丝氨酸/苏氨酸激酶，参与多种对维持细胞内稳态至关重要的作用。CK2 表达水平的升高导致调节转录的关键信号通路失调，并与癌症有关。报道称，三磷酸腺苷竞争性抑制剂 CX-4945 在多种癌细胞系中表现出广谱抗增殖活性。尽管已经报道了 CX-4945 的酶 IC（50），但与 CK2α 结合的热力学和结构基础仍不清楚。本文分别报道了人 CK2α 与 CX-4945 和腺苷酰磷酸酰胺复合物的晶体结构，分辨率分别为 2.7 和 1.3 Å。还描述了 CX-4945 结合的生物物理分析。这些数据为针对这一新兴癌症靶点设计更有效的抑制剂提供了结构依据。
