4ib5

Publication Abstract from PubMed

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 (CK2alpha) attached to a dimer of noncatalytic subunits (CK2beta). A druggable cavity at the CK2beta interface of CK2alpha allows the design of small molecules disturbing the CK2alpha/CK2beta interaction and thus affecting activity, stability, and substrate specificity. We describe here the first structure of CK2alpha with an effective CK2beta-competitive compound, namely, a 13-meric cyclic peptide derived from the C-terminal CK2beta 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 CK2alpha, stimulates its catalytic activity, and reduces effectively the CK2alpha/CK2beta affinity. The results provide a thermodynamic and structural rationalization of the peptide's CK2beta-competitive functionality and pave thus the way to a peptidomimetic drug addressing the CK2alpha/CK2beta interaction.

First Structure of Protein Kinase CK2 Catalytic Subunit with an Effective CK2beta-Competitive Ligand.,Raaf J, Guerra B, Neundorf I, Bopp B, Issinger OG, Jose J, Pietsch M, Niefind K ACS Chem Biol. 2013 Mar 18. PMID:23474121^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.