Crystal structure of human CK2α at 1.06 Å resolution

Abstract

The Ser/Thr kinase CK2 consists of two catalytic subunits (CK2 ) and a dimer of the regulatory subunits (CK2 ), and is a ubiquitous enzyme that regulates growth, proliferation and the survival of cells. CK2 is a remarkable drug target for potentially treating a wide variety of tumours and glomerulonephritis. The purified CK2 protein was crystallized using ethylene glycol as a precipitant. The crystal structure of CK2 with 21 loci of alternative conformations, including a niacin, 19 ethylene glycols and 346 waters, was determined at 1.06 Å resolution to an R work of 14.0% (R free = 16.5%). The alternative ensemble in the internal hydrophobic core underpins the plasticity of the D-helix responsible for the regulation of ATP/GTP binding. The clear density map indicates that a niacin molecule, contained in the Escherichia coli culture medium, binds to the ATP binding site. An ethylene glycol molecule binds in the hydrophobic pocket lateral to the D-helix forming the rim of the active site. The other ethylene glycol molecules occupy physiologically significant sites, including the CK2 binding interface and substrate binding site, as well as the gap in the crystal packing. Together with water molecules in the active site, these structural insights should facilitate drug discovery.

Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches

“…This cryptic site was then used to develop a new CK2 α inhibitor with high nanomolar affinity [41]. Interestingly, in one structure of CK2 α (PDB ID 3WAR), it was observed that two ethylene glycol molecules were bound at the entrance of the partially opened α D pocket [41, 42] further supporting our concept of using small glycols to identify cryptic sites in protein targets leaving to the use the identified cryptic sites for drug-design purposes. Another crystallography study of protein CK2 α [42] has shown several ethylene glycol molecules occupying physiologically significant sites of CK2 α suggesting their use in computational methods for binding site determination.…”

Thermodynamics parameters for binding of halogenated benzotriazole inhibitors of human protein kinase CK2α

“…The internal variance in strongly binding ligands of ~10 kJ/mol (TBBt, 4,5,6-Br 3 Bt, 5,6-Br 2 Bt, 5-BrBt, and most likely 4,5,7-Br 3 Bt) must consequently be attributed to other types of specific ligand-protein interactions, including the eventual contribution of halogen bonding observed in the crystal structure of TBBt bound to maize CK2α [36]. bound to maize CK2α (PDB: 1j91 [57]) and the highest-resolution structures of human CK2α (PDB: 3at2 [82], 3bqc [83], 3h30 [84], 3nsz [85], 3pe1 [86], 3war [87], 4kwp [88]). .…”

“…The ensemble of seven structures was modeled by homology, based on the highestresolution structures of human CK2α found in the Protein Data Bank (PDB: 3at2 [82], 3bqc [83], 3h30 [84], 3nsz [85], 3pe1 [86], 3war [87], 4kwp [88]). Each was then structurally aligned with the complex of TBBt with maize CK2α (PDB: 1j91 [57]), using the Mustang algorithm [89] implemented in the Yasara Structure Package [90].…”

Converting Potent Indeno[1,2-b]indole Inhibitors of Protein Kinase CK2 into Selective Inhibitors of the Breast Cancer Resistance Protein ABCG2

“…Recent structural insights of CK2α, CK2β and CK2 (quaternary structure of CK2) gave further knowledge to perform tailor-made compounds. [9][10][11] Thus CK2 is becoming an important drug target for the 21 st century as mentioned by E.G. Krebs in 1999.…”