Protein kinase CK2 is one of the most challenging members of the kinase superfamily. Although this protein has been the subject of intensive studies over the last 50 years, very little is known about its precise biological function and mode of regulation. The CK2 holoenzyme is composed of two catalytic α- and two regulatory β-subunits and is classified as an acidophilic Ser/Thr kinase. Unique properties of the catalytic α-subunit are its intrinsic activity and high pleiotropicity. CK2 is supposed to be involved in many fundamental aspects of the normal cell life as well as in degenerative processes that can lead to cancer or tumor pathologies. This makes CK2 an interesting target for the development of inhibitors with pharmacological perspectives. The inhibitors studied are directed to the CK2 ATP-binding site that, among the known kinases, carries some distinctive features as indicated by its ability to use both ATP and GTP as co-substrates and the low susceptiveness to staurosporine inhibition. On the basis of three-dimensional crystal structures, we describe and discuss the effects of the binding to CK2 of inhibitors with a potency in the low micromolar range belonging to different chemical families, i.e., benzotriazoles, anthraquinones, and quinazolinones. The overall structure of the protein is poorly affected by the binding of these small molecules. In the proximity of the binding site, the most affected residues are Asn118, His160, Met163, and those of the glycine-rich loop. Two of the inhibitors, namely tetrabromo-2-benzotriazolo (TBB) and the indoloquinazolinone IQA, display a significant selectivity among panels of tens of different kinases. An important common energetic contribution to the inhibitors' binding is ascribed to the hydrophobic interaction with the apolar surface region of the CK2 binding cleft. The shape and the reduced dimension of the CK2 active site in comparison with other kinases are essential in explaining the selectivity of these inhibitors as well as the anomalous low potency of staurosporine.

Inhibitors of protein kinase CK2: structural aspects

BATTISTUTTA, ROBERTO;SARNO, STEFANIA;ZANOTTI, GIUSEPPE
2005

Abstract

Protein kinase CK2 is one of the most challenging members of the kinase superfamily. Although this protein has been the subject of intensive studies over the last 50 years, very little is known about its precise biological function and mode of regulation. The CK2 holoenzyme is composed of two catalytic α- and two regulatory β-subunits and is classified as an acidophilic Ser/Thr kinase. Unique properties of the catalytic α-subunit are its intrinsic activity and high pleiotropicity. CK2 is supposed to be involved in many fundamental aspects of the normal cell life as well as in degenerative processes that can lead to cancer or tumor pathologies. This makes CK2 an interesting target for the development of inhibitors with pharmacological perspectives. The inhibitors studied are directed to the CK2 ATP-binding site that, among the known kinases, carries some distinctive features as indicated by its ability to use both ATP and GTP as co-substrates and the low susceptiveness to staurosporine inhibition. On the basis of three-dimensional crystal structures, we describe and discuss the effects of the binding to CK2 of inhibitors with a potency in the low micromolar range belonging to different chemical families, i.e., benzotriazoles, anthraquinones, and quinazolinones. The overall structure of the protein is poorly affected by the binding of these small molecules. In the proximity of the binding site, the most affected residues are Asn118, His160, Met163, and those of the glycine-rich loop. Two of the inhibitors, namely tetrabromo-2-benzotriazolo (TBB) and the indoloquinazolinone IQA, display a significant selectivity among panels of tens of different kinases. An important common energetic contribution to the inhibitors' binding is ascribed to the hydrophobic interaction with the apolar surface region of the CK2 binding cleft. The shape and the reduced dimension of the CK2 active site in comparison with other kinases are essential in explaining the selectivity of these inhibitors as well as the anomalous low potency of staurosporine.
Inhibitors of protein kinases and protein phosphatases - Handbook of experimental pharmacology
9783540212423
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2438398
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