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Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2 alpha, the catalytic subunit of human protein kinase CK2, or its paralog CK2 alpha' in complex with two ATP-competitive inhibitors-based on either a flavonol or a thieno[2,3-d]pyrimidine framework-are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix alpha D region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2 alpha and CK2 alpha'. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations.

CK2 is a Ser/Thr kinase recruited by tumor cells to avoid cell death. 4'-Carboxy-6,8-dibromo-flavonol (FLC26) is a nanomolar CK2 inhibitor reducing the physiological phosphorylation of CK2 biomarkers and inducing cell death. Its binding mode to the ATP site was predicted to depend primarily on noncovalent interactions not comprising halogen bonds. We confirm this by two independent cocrystal structures which additionally show that FLC26 is selective for an open, protein kinase-untypical conformation of the hinge/helix alpha D region. The structures suggest how the bromo substituents, found previously in lead optimization studies, contribute to the inhibitory efficacy. In this context, one of the complex structures, obtained by crystallization with the kosmotropic salt NaCl, revealed an unconventional pi-halogen bond between the 8-bromo substituent of FLC26 and an aromatic side chain which is absent under low-salt conditions. The kosmotropic salt sensitivity of pi-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.