5ts8 | pdb_00005ts8

Z. MAYS CK2 KINASE ALPHA SUBUNIT IN COMPLEX WITH THE ATP-COMPETITIVE INHIBITOR 5,6-DIBROMOBENZOTRIAZOLE

spinqualitylabelsall models 5ts8, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ts8 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 7M0, ACT, BME, DMS, EDO, FMT, GOL, TLA Related: 4rkl, 1j91, 1daw, 4kwp, 1p5e, 2oxy Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The interaction of human CK2alpha (hCK2alpha) with nine halogenated benzotriazoles, TBBt and its analogues representing all possible patterns of halogenation on the benzene ring of benzotriazole, was studied by biophysical methods. Thermal stability of protein-ligand complexes, monitored by calorimetric (DSC) and optical (DSF) methods, showed that the increase in the mid-point temperature for unfolding of protein-ligand complexes (i.e. potency of ligand binding to hCK2alpha) follow the inhibitory activities determined by biochemical assays. The dissociation constant for the ATP-hCK2alpha complex was estimated with the aid of microscale thermophoresis (MST) as 4.3+/-1.8 muM, and MST-derived dissociation constants determined for halogenated benzotriazoles, when converted according to known ATP concentrations, perfectly reconstruct IC50 values determined by the biochemical assays. Ligand-dependent quenching of tyrosine fluorescence, together with molecular modeling and DSC-derived heats of unfolding, support the hypothesis that halogenated benzotriazoles bind in at least two alternative orientations, and those that are efficient hCK2alpha inhibitors bind in the orientation which TBBt adopts in its complex with maize CK2alpha. DSC-derived apparent heat for ligand binding (DeltaDeltaHbind) is driven by intermolecular electrostatic interactions between Lys68 and the triazole ring of the ligand, as indicated by a good correlation between DeltaDeltaHbind and ligand pKa. Overall results, additionally supported by molecular modeling, confirm that a balance of hydrophobic and electrostatic interactions contribute predominantly (~40 kJ/mol), relative to possible intermolecular halogen/hydrogen bonding (less than 10 kJ/mol), in binding of halogenated benzotriazoles to the ATP-binding site of hCK2alpha. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. Thermodynamics parameters for binding of halogenated benzotriazole inhibitors of human protein kinase CK2alpha.,Winiewska M, Kucinska K, Makowska M, Poznanski J, Shugar D Biochim Biophys Acta. 2015 Oct;1854(10 Pt B):1708-17. doi:, 10.1016/j.bbapap.2015.04.004. Epub 2015 Apr 17. PMID:25891901 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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