6TLS

HUMAN CK2 KINASE ALPHA SUBUNIT IN COMPLEX WITH THE ATP-COMPETITIVE INHIBITOR 4,6-DIBROMOBENZOTRIAZOLE

Summary for 6TLS

• Entry DOI: 10.2210/pdb6tls/pdb
• Descriptor: Casein kinase II subunit alpha, 5,7-bis(bromanyl)-1~{H}-benzotriazole, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: ck2, casein kinase 2, inhibitor, bromo-benzotriazole, halogen bond, transferase-transferase inhibitor complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 47139.91

Authors

Czapinska, H.,Piasecka, A.,Winiewska-Szajewska, M.,Bochtler, M.,Poznanski, J. (deposition date: 2019-12-03, release date: 2020-12-16, Last modification date: 2024-01-24)

Primary citation

Czapinska, H.,Winiewska-Szajewska, M.,Szymaniec-Rutkowska, A.,Piasecka, A.,Bochtler, M.,Poznanski, J.
Halogen Atoms in the Protein-Ligand System. Structural and Thermodynamic Studies of the Binding of Bromobenzotriazoles by the Catalytic Subunit of Human Protein Kinase CK2.
J.Phys.Chem.B, 125:2491-2503, 2021

PubMed Abstract: Binding of a family of brominated benzotriazoles to the catalytic subunit of human protein kinase CK2 (hCK2α) was used as a model system to assess the contribution of halogen bonding to protein-ligand interaction. CK2 is a constitutively active pleiotropic serine/threonine protein kinase that belongs to the CMGC group of eukaryotic protein kinases (EPKs). Due to the addiction of some cancer cells, CK2 is an attractive and well-characterized drug target. Halogenated benzotriazoles act as ATP-competitive inhibitors with unexpectedly good selectivity for CK2 over other EPKs. We have characterized the interaction of bromobenzotriazoles with hCK2α by X-ray crystallography, low-volume differential scanning fluorimetry, and isothermal titration calorimetry. Properties of free ligands in solution were additionally characterized by volumetric and RT-HPLC measurements. Thermodynamic data indicate that the affinity increases with bromo substitution, with greater contributions from 5- and 6-substituents than 4- and 7-substituents. Except for 4,7-disubstituted compounds, the bromobenzotriazoles adopt a canonical pose with the triazole close to lysine 68, which precludes halogen bonding. More highly substituted benzotriazoles adopt many additional noncanonical poses, presumably driven by a large hydrophobic contribution to binding. Some noncanonical ligand orientations allow the formation of halogen bonds with the hinge region. Consistent with a predominantly hydrophobic interaction, the isobaric heat capacity decreases upon ligand binding, the more so the higher the substitution.

PubMed: 33689348
DOI: 10.1021/acs.jpcb.0c10264

Experimental method

X-RAY DIFFRACTION (1.46 Å)