1OM1

Crystal structure of maize CK2 alpha in complex with IQA

Summary for 1OM1

• Entry DOI: 10.2210/pdb1om1/pdb
• Descriptor: Casein kinase II, alpha chain, (5-OXO-5,6-DIHYDRO-INDOLO[1,2-A]QUINAZOLIN-7-YL)-ACETIC ACID (3 entities in total)
• Functional Keywords: ck2, iqa, inhibitor, zea mays, transferase
• Biological source: Zea mays
• Total number of polymer chains: 1
• Total formula weight: 39583.45

Authors

Battistutta, R.,De Moliner, E.,Zanotti, G. (deposition date: 2003-02-24, release date: 2004-02-24, Last modification date: 2024-02-14)

Primary citation

Sarno, S.,de Moliner, E.,Ruzzene, M.,Pagano, M.A.,Battistutta, R.,Bain, J.,Fabbro, D.,Schoepfer, J.,Elliott, M.,Furet, P.,Meggio, F.,Zanotti, G.,Pinna, L.A.
Biochemical and three-dimensional-structural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo-(1,2-a)quinazolin-7-yl]acetic acid (IQA).
Biochem.J., 374:639-646, 2003

PubMed Abstract: IQA [[5-oxo-5,6-dihydro-indolo(1,2-a)quinazolin-7-yl]acetic acid] is a novel ATP/GTP site-directed inhibitor of CK2 ('casein kinase 2'), a pleiotropic and constitutively active protein kinase whose activity is abnormally high in transformed cells. The K (i) value of IQA (0.17 microM) is lower than those of other CK2 inhibitors reported so far. Tested at 10 microM concentration in the presence of 100 microM ATP, IQA almost suppresses CK2 activity in vitro, whereas it is ineffective or weakly effective on a panel of 44 protein kinases and on phosphoinositide 3-kinase. In comparison, other CK2 inhibitors, notably apigenin and quercetin, are more promiscuous. The in vivo efficacy of IQA has been assessed by using the fact that treatment of Jurkat cells with IQA inhibits endogenous CK2 in a dose-dependent manner. IQA has been co-crystallized with maize CK2alpha, which is >70% identical with its human homologue, and the structure of the complex has been determined at 1.68 A (1 A=0.1 nm) resolution. The inhibitor lies in the same plane occupied by the purine moiety of ATP with its more hydrophobic side facing the hinge region. Major contributions to the interaction are provided by hydrophobic forces and non-polar interactions involving the aromatic portion of the inhibitor and the hydrophobic residues surrounding the ATP-binding pocket, with special reference to the side chains of V53 (Val53), I66, M163 and I174. Consequently, mutants of human CK2alpha in which either V66 (the homologue of maize CK2alpha I66) or I174 is replaced by alanine are considerably less sensitive to IQA inhibition when compared with wild-type. These results provide new tools for deciphering the enigmatic role of CK2 in living cells and may pave the way for the development of drugs depending on CK2 activity.

PubMed: 12816539
DOI: 10.1042/BJ20030674

Experimental method

X-RAY DIFFRACTION (1.68 Å)