title: A Note of Caution on the Role of Halogen Bonds for Protein Kinase/Inhibitor Recognition Suggested by High- And Low-Salt CK2α Complex Structures.
abstract: 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 αD 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 π-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 π-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.
authors.affiliation: †University of Southern Denmark, Department of Biochemistry and Molecular Biology, Campusvej 55, DK-5230 Odense, Denmark.
authors.forename: Barbara
authors.initials: B
authors.lastname: Guerra
authors.affiliation: ‡University of Cologne, Institute of Biochemistry, Otto-Fischer-Str. 12-14, D-50674 Cologne, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Bischoff
authors.affiliation: §Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., Kyiv 03680, Ukraine.
authors.forename: Volodymyr G
authors.initials: VG
authors.lastname: Bdzhola
authors.affiliation: §Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., Kyiv 03680, Ukraine.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Yarmoluk
authors.affiliation: †University of Southern Denmark, Department of Biochemistry and Molecular Biology, Campusvej 55, DK-5230 Odense, Denmark.
authors.forename: Olaf-Georg
authors.initials: OG
authors.lastname: Issinger
authors.affiliation: §Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Str., Kyiv 03680, Ukraine.
authors.forename: Andriy G
authors.initials: AG
authors.lastname: Golub
authors.affiliation: ‡University of Cologne, Institute of Biochemistry, Otto-Fischer-Str. 12-14, D-50674 Cologne, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Niefind
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054879:Halogenation; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D012492:Salts / Q000737:chemistry
chemical_list: D047428:Protein Kinase Inhibitors; D012492:Salts; D000255:Adenosine Triphosphate; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II