3PE1

Crystal structure of human protein kinase CK2 alpha subunit in complex with the inhibitor CX-4945

Summary for 3PE1

• Entry DOI: 10.2210/pdb3pe1/pdb
• Related: 3FL5 3PE2
• Descriptor: Casein kinase II subunit alpha, 5-[(3-chlorophenyl)amino]benzo[c][2,6]naphthyridine-8-carboxylic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase, ck2-inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40878.86

Authors

Battistutta, R.,Papinutto, E.,Lolli, G.,Pierre, F.,Haddach, M.,Ryckman, D.M. (deposition date: 2010-10-25, release date: 2011-09-07, Last modification date: 2023-09-06)

Primary citation

Battistutta, R.,Cozza, G.,Pierre, F.,Papinutto, E.,Lolli, G.,Sarno, S.,O'Brien, S.E.,Siddiqui-Jain, A.,Haddach, M.,Anderes, K.,Ryckman, D.M.,Meggio, F.,Pinna, L.A.
Unprecedented selectivity and structural determinants of a new class of protein kinase CK2 inhibitors in clinical trials for the treatment of cancer.
Biochemistry, 50:8478-8488, 2011

PubMed Abstract: 5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer, is representative of a new class of CK2 inhibitors with K(i) values in the low nanomolar range and unprecedented selectivity versus other kinases. Here we present the crystal structure of the complexes of CX-4945 and two analogues (CX-5011 and CX-5279) with the catalytic subunit of human CK2. Consistent with their ATP-competitive mode of inhibition, all three compounds bind in the active site of CK2 (type I inhibitors). The tricyclic scaffold of the inhibitors superposes on the adenine of ATP, establishing multiple hydrophobic interactions with the binding cavity. The more extended scaffold, as compared to that of ATP, allows the carboxylic function, shared by all three ligands, to penetrate into the deepest part of the active site where it makes interactions with conserved water W1 and Lys-68, thus accounting for the crucial role of this negatively charged group in conferring high potency to this class of inhibitors. The presence of a pyrimidine in CX-5011 and in CX-5279 instead of a pyridine (as in CX-4945) ring is likely to account for the higher specificity of these compounds whose Gini coefficients, calculated by profiling them against panels of 102 and/or 235 kinases, are significantly higher than that of CX-4945 (0.735 and 0.755, respectively, vs 0.615), marking the highest selectivity ever reported for CK2 inhibitors.

PubMed: 21870818
DOI: 10.1021/bi2008382

Experimental method

X-RAY DIFFRACTION (1.6 Å)