Raaf Jennifer, Brunstein Elena, Issinger Olaf-Georg, Niefind Karsten
Institut für Biochemie, Universität zu Köln, Zülpicher Str. 47, D-50674 Köln, Germany.
Chem Biol. 2008 Feb;15(2):111-7. doi: 10.1016/j.chembiol.2007.12.012.
The Ser/Thr kinase CK2 (previously called casein kinase 2) is composed of two catalytic chains (CK2 alpha) attached to a dimer of noncatalytic subunits (CK2 beta). CK2 is involved in suppression of apoptosis, cell survival, and tumorigenesis. To investigate these activities and possibly affect them, selective CK2 inhibitors are required. An often-used CK2 inhibitor is 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). In a complex structure with human CK2 alpha, DRB binds to the canonical ATP cleft, but additionally it occupies an allosteric site that can be alternatively filled by glycerol. Inhibition kinetic studies corroborate the dual binding mode of the inhibitor. Structural comparisons reveal a surprising conformational plasticity of human CK2 alpha around both DRB binding sites. After local rearrangement, the allosteric site serves as a CK2 beta interface. This opens the potential to construct molecules interfering with the CK2 alpha/CK2 beta interaction.
丝氨酸/苏氨酸激酶CK2（以前称为酪蛋白激酶2）由两个催化链（CK2α）与一个非催化亚基二聚体（CK2β）相连组成。CK2参与细胞凋亡的抑制、细胞存活和肿瘤发生。为了研究这些活性并可能对其产生影响，需要选择性CK2抑制剂。一种常用的CK2抑制剂是5,6-二氯-1-β-D-呋喃核糖基苯并咪唑（DRB）。在与人类CK2α的复合物结构中，DRB结合到典型的ATP裂隙处，但此外它还占据一个变构位点，该位点也可被甘油占据。抑制动力学研究证实了抑制剂的双重结合模式。结构比较揭示了人类CK2α在两个DRB结合位点周围令人惊讶的构象可塑性。局部重排后，变构位点成为CK2β界面。这为构建干扰CK2α/CK2β相互作用的分子开辟了可能性。
