First Structure of Protein Kinase CK2 Catalytic Subunit with an Effective CK2β-Competitive Ligand

The constitutively active Ser/Thr kinase CK2 (casein kinase 2) is used by tumor cells to acquire apoptosis resistance. CK2 exists as a heterotetrameric holoenzyme with two catalytic chains (CK2 alpha) attached to a dimer of noncatalytic subunits (CK2 beta). A druggable cavity at the CK2 beta interface of CK2 alpha allows the design of small molecules disturbing the CK2 alpha/CK2 beta interaction and thus affecting activity, stability, and substrate specificity. We describe here the first structure of CK2 alpha with an effective CK2 beta-competitive compound, namely, a 13-meric cyclic peptide derived from the C-terminal CK2 beta segment. Some well-ordered water molecules not visible in CK2 holoenzyme structures were detected at the interface. Driven mainly by enthalpy, the peptide binds with submicromolar affinity to CK2 alpha, stimulates its catalytic activity, and reduces effectively the CK2 alpha/CK2 beta affinity. The results provide a thermodynamic and structural rationalization of the peptide's Ck2 beta-competitive functionality and pave thus the way to a peptidomimetic drug addressing the CK2 alpha/CK2 beta interaction.