부산대학교 도서관

Casein kinase 2 (CK2) is a vital protein kinase that consists of two catalytic subunits (CK2α1 and/or CK2α2) and two regulatory subunits (CK2β). CK2α1 is a drug target for nephritis and cancers, while CK2α2 is a serious off-target because its inhibition causes testicular toxicity. High similarity between the isozymes CK2α1 and CK2α2 make it difficult to design CK2α1-specific inhibitors. Herein, the crystal structures of CK2α1 and CK2α2 complexed with a 3-amino-pyrazole inhibitor revealed the remarkable differences in the protein–inhibitor interaction modes. This inhibitor bound to the ATP binding sites of both isozymes in apparently distinct orientations. In addition, another molecule of this inhibitor bound to CK2α1, but not to CK2α2, at the CK2β protein–protein interface. Binding energy calculations and biochemical experiments suggested that this inhibitor possesses the conventional ATP-competitive characteristics with moderate allosteric function in a molecular glue mechanism. These results will assist the potential design of potent and selective CK2α1 inhibitors. • CK2α1 is a drug target for serious diseases such as cancer while CK2α2 is off-target. • Crystal structures of CK2α1and CK2α2 complexed with an inhibitor were determined. • The inhibitor bound to the ATP site of both isozymes in distinct orientations. • The inhibitor also bound to the allosteric site of CK2α1 but not to that of CK2α2. • These findings will promote to produce potent and selective CK2α1 inhibitors. [ABSTRACT FROM AUTHOR]