Department of Chemical Sciences, University of Padua, Padova, Italy.
ACS Chem Biol. 2012 Jul 20;7(7):1158-63. doi: 10.1021/cb300054n. Epub 2012 Apr 20.
CK2 is a Ser/Thr protein kinase essential for cell viability whose activity is anomalously high in several cancers. CK2 is a validated target for cancer therapy with one small molecule inhibitor in phase I clinical trials. This enzyme is not regulated by mechanisms common to other protein kinases, and how its activity is controlled is still unclear. We present a new crystal structure of the CK2 holoenzyme that supports an autoinhibitory mechanism of regulation whereby the β-subunit plays an essential role in the formation of inactive polymeric assemblies. The derived structural model of (down)regulation by aggregation contributes to the interpretation of biochemical and functional data and paves the way for new strategies in the modulation of CK2 activity and for the design of non-ATP-competitive inhibitors targeting the interaction between the α catalytic and the β regulatory subunits.
CK2 是一种丝氨酸/苏氨酸蛋白激酶，对细胞存活至关重要，其活性在多种癌症中异常升高。CK2 是癌症治疗的一个经过验证的靶点，目前有一种小分子抑制剂正在进行 I 期临床试验。该酶不受其他蛋白激酶常见机制的调节，其活性如何控制仍不清楚。我们提出了 CK2 全酶的一个新晶体结构，支持一个自动抑制调节机制，其中β亚基在形成无活性的聚合组装体中起着重要作用。通过聚集进行（下调）调节的推导结构模型有助于解释生化和功能数据，并为调节 CK2 活性的新策略以及针对 α 催化和 β 调节亚基之间相互作用的非 ATP 竞争性抑制剂的设计铺平道路。
