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Inhibitors of Protein Kinases and Protein Phosphates pp 125–155Cite as

Inhibitors of Protein Kinase CK2: Structural Aspects

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 167))

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., ben zotriazoles, 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.

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References

  • Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12:226–230

    Article  PubMed  CAS  Google Scholar 

  • Ali AM, Ismail NH, Mackeen MM, Yazan LS, Mohamed SM, Ho ASH, Lajis NH (2000) Antiviral, cytotoxic and antimicrobial activities of anthraquinones isolated from the roots of Morinda elliptica. Pharm Biol 38:298–301

    Article  CAS  Google Scholar 

  • Battistutta R, Sarno S, De Moliner E, Papinutto E, Zanotti G, Pinna LA (2000) The replacement of ATP by the competitive inhibitor emodin induces conformational modifications in the catalytic site of protein kinase CK2. J Biol Chem 275:29618–29622

    Article  PubMed  CAS  Google Scholar 

  • Battistutta R, De Moliner E, Sarno S, Zanotti G, Pinna LA (2001) Structural features underlying selective inhibition of protein kinase CK2 by ATP site-directed tetrabromo-2-benzotriazole. Protein Sci 10:2200–2206

    Article  PubMed  CAS  Google Scholar 

  • Buchou T, Vernet M, Blond O, Jensen HH, Pointu H, Olsen BB, Cochet C, Issinger OG, Boldyreff B (2003) Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23:908–915

    Article  PubMed  CAS  Google Scholar 

  • Burnett G, Kennedy EP (1954) The enzymatic phosphorylation of proteins. J Biol Chem 211:969–980

    PubMed  CAS  Google Scholar 

  • Chan TC, Chang CJ, Koonchanok NM, Geahlen RL (1993) Selective inhibition of the growth of ras-transformed human bronchial epithelial cells by emodin, a protein-tyrosine kinase inhibitor. Biochem Biophys Res Commun 193:1152–1158

    PubMed  CAS  Google Scholar 

  • Chantalat L, Leroy D, Filhol O, Nueda A, Benitez MJ, Chambaz EM, Cochet C, Dideberg O (1999) Crystal structure of the human protein kinase CK2 regulatory subunit reveals its zinc finger-mediated dimerization. EMBO J 18:2930–2940

    Article  PubMed  CAS  Google Scholar 

  • Chardot T, Shen H, Meunier JC (1995) Dual specificity of casein kinase II from the yeast Yarrowia lipolytica. C R Acad Sci III 318:937–942

    PubMed  CAS  Google Scholar 

  • Cohen P (2002) Protein kinases: the major drug targets of the twenty-first century? Nat Rev Drug Discov 1:309–315

    Article  PubMed  CAS  Google Scholar 

  • Davis ST, Benson BG, Bramson HN, Chapman DE, Dickerson SH, Dold KM, Eberwein DJ, Edelstein M, Frye SV, Gampe Jr RT, Griffin RJ, Harris PA, Hassell AM, Holmes WD, Hunter RN, Knick VB, Lackey K, Lovejoy B, Luzzio MJ, Murray D, Parker P, Rocque WJ, Shewchuk L, Veal JM, Walker DH, Kuyper LF (2001) Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors. Science 291:134–137

    Article  PubMed  CAS  Google Scholar 

  • De Moliner E, Moro S, Sarno S, Zagotto G, Zanotti G, Pinna LA, Battistutta R (2003) Inhibition of protein kinase CK2 by anthraquinone-related compounds. A structural insight. J Biol Chem 278:1831–1836

    PubMed  Google Scholar 

  • Donella-Deana A, Cesaro L, Sarno S, Brunati AM, Ruzzene M, Pinna LA (2001) Autocatalytic tyrosine-phosphorylation of protein kinase CK2 alpha and alpha’ subunits: implication of Tyr182. Biochem J 357:563–567

    Article  PubMed  CAS  Google Scholar 

  • Engh RA, Bossemeyer D (2002) Structural aspects of protein kinase control-role of conformational flexibility. Pharmacol Ther 93:99–111

    Article  PubMed  CAS  Google Scholar 

  • Ermakova I, Boldyreff B, Issinger OG, Niefind K (2003) Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit. J Mol Biol 330:925–934

    Article  PubMed  CAS  Google Scholar 

  • Faust M, Montenarh M (2000) Subcellular localization of protein kinase CK2. A key to its function? Cell Tissue Res 301:329–340

    Article  PubMed  CAS  Google Scholar 

  • Fraser AG, Kamath RS, Zipperlen P, Martinez-Campos M, Sohrmann M, Ahringer J (2000) Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408:325–330

    PubMed  CAS  Google Scholar 

  • Fredenhagen A, Mett H, Meyer T, Buchdunger E, Regenass U, Roggo BE, Petersen F (1995) Protein tyrosine kinase and protein kinase C inhibition by fungal anthraquinones related to emodin. J Antibiot Tokyo 48:1355–1358

    PubMed  CAS  Google Scholar 

  • Garcia-Echeverria C, Traxler P, Evans DB (2000) ATP site-directed competitive and irreversible inhibitors of protein kinases. Med Res Rev 20:28–57

    PubMed  CAS  Google Scholar 

  • Goel S, Mani S, Perez Soler R (2002) Tyrosine kinase inhibitors: a clinical perspective. Curr Oncol Rep 4:9–19

    PubMed  Google Scholar 

  • Graham KC, Litchfield DW (2000) The regulatory beta subunit of protein kinase CK2 mediates formation of tetrameric CK2 complexes. J Biol Chem 275:5003–5010

    PubMed  CAS  Google Scholar 

  • Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim SH, Lockhart DJ, Schultz PG (1998) Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281:533–538

    Article  PubMed  CAS  Google Scholar 

  • Guerra B, Issinger OG (1999) Protein kinase CK2 and its role in cellular proliferation, development and pathology. Electrophoresis 20:391–408

    Article  PubMed  CAS  Google Scholar 

  • Hanks SK, Hunter T (1995) Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J 9:576–596

    PubMed  CAS  Google Scholar 

  • Hardcastle IR, Golding BT, Griffin RJ (2002) Designing inhibitors of cyclin-dependent kinases. Annu Rev Pharmacol Toxicol 42:325–348

    Article  PubMed  CAS  Google Scholar 

  • Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275–282

    Article  PubMed  CAS  Google Scholar 

  • Jayasuriya H, Koonchanok NM, Geahlen RL, McLaughlin JL, Chang CJ (1992) Emodin, a protein tyrosine kinase inhibitor from Polygonum cuspidatum. J Nat Prod 55:696–698

    Article  PubMed  CAS  Google Scholar 

  • Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massague J, Pavletich NP (1995) Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 376:313–320

    Article  PubMed  CAS  Google Scholar 

  • Johnson LN, Noble ME, Owen DJ (1996) Active and inactive protein kinases: structural basis for regulation. Cell 85:149–158

    Article  PubMed  CAS  Google Scholar 

  • Litchfield DW (2003) Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 369:1–15

    Article  PubMed  CAS  Google Scholar 

  • Manning G, Plowman GD, Hunter T, Sudarsanam S (2002a) Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 27:514–520

    Article  PubMed  CAS  Google Scholar 

  • Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002b) The protein kinase complement of the human genome. Science 298:1912–1934

    Article  PubMed  CAS  Google Scholar 

  • Marin O, Meggio F, Sarno S, Cesaro L, Pagano MA, Pinna LA (1999) Tyrosine versus serine/threonine phosphorylation by protein kinase casein kinase-2. A study with peptide substrates derived from immunophilin Fpr3. J Biol Chem 274:29260–29265

    Article  PubMed  CAS  Google Scholar 

  • Meggio F, Marin O, Pinna LA (1994) Substrate specificity of protein kinase CK2. Cell Mol Biol Res 40:401–409

    PubMed  CAS  Google Scholar 

  • Meggio F, Donella Deana A, Ruzzene M, Brunati AM, Cesaro L, Guerra B, Meyer T, Mett H, Fabbro D, Furet P, Dobrowolska G, Pinna LA (1995) Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. Eur J Biochem 234:317–322

    Article  PubMed  CAS  Google Scholar 

  • Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17:349–368

    Article  PubMed  CAS  Google Scholar 

  • Niefind K, Guerra B, Pinna LA, Issinger OG, Schomburg D (1998) Crystal structure of the catalytic subunit of protein kinase CK2 from Zea mays at 2.1 Åresolution. EMBO J 17:2451–2462

    Article  PubMed  CAS  Google Scholar 

  • Niefind K, Putter M, Guerra B, Issinger OG, Schomburg D (1999) GTP plus water mimic ATP in the active site of protein kinase CK2. Nat Struct Biol 6:1100–1103

    Article  PubMed  CAS  Google Scholar 

  • Niefind K, Guerra B, Ermakowa I, Issinger OG (2001) Crystal structure of human protein kinase CK2: insights into basic properties of the CK2 holoenzyme. EMBO J 20:5320–5331

    Article  PubMed  CAS  Google Scholar 

  • Padmanabha R, Chen Wu JL, Hanna DE, Glover CV (1990) Isolation, sequencing, and disruption of the yeast CKA2 gene: casein kinase II is essential for viability in Saccharomyces cerevisiae. Mol Cell Biol 10:4089–4099

    PubMed  CAS  Google Scholar 

  • Parang K, Cole PA (2002) Designing bisubstrate analog inhibitors for protein kinases. Pharmacol Ther 93:145–157

    Article  PubMed  CAS  Google Scholar 

  • Parang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA (2001) Mechanismbased design of a protein kinase inhibitor. Nat Struct Biol 8:37–41

    PubMed  CAS  Google Scholar 

  • Pechkova E, Zanotti G, Nicolini C (2003) Three-dimensional atomic structure of a catalytic subunit mutant of human protein kinase CK2. Acta Cryst D 59:2133–2139

    Article  CAS  Google Scholar 

  • Pinna LA (2002) Protein kinase CK2: a challenge to canons. J Cell Sci 115:3873–3878

    Article  PubMed  CAS  Google Scholar 

  • Pinna LA, Meggio F (1997) Protein kinase CK2 (“casein kinase-2”) and its implication in cell division and proliferation. Prog Cell Cycle Res 3:77–97

    PubMed  CAS  Google Scholar 

  • Sarno S, Vaglio P, Meggio F, Issinger OG, Pinna LA (1996) Protein kinase CK2 mutants defective in substrate recognition. Purification and kinetic analysis. J Biol Chem 271:10595–10601

    PubMed  CAS  Google Scholar 

  • Sarno S, Moro S, Meggio F, Zagotto G, Dal Ben D, Ghisellini P, Battistutta R, Zanotti G, Pinna LA (2002) Toward the rational design of protein kinase casein kinase-2 inhibitors. Pharmacol Ther 93:159–168

    Article  PubMed  CAS  Google Scholar 

  • Sarno S, De Moliner E, Ruzzene M, Pagano MA, Battistutta R, Bain J, Fabbro D, Schoepfer J, Elliott M, Furet P, Meggio F, Zanotti G, Pinna LA (2003) Biochemical and 3D-structural data on the specific inhibition of protein kinase CK2 by (5-oxo-5,6-dihydro-indolo(1,2-a)quinazolin-7-yl)acetic acid (IQA). Biochem J 374:639–646

    Article  PubMed  CAS  Google Scholar 

  • Sarno S, Reddy H, Meggio F, Ruzzene M, Davies SP, Donella Deana A, Shugar D, Pinna LA (2001) Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 (’casein kinase-2’). FEBS Lett 496:44–48

    Article  PubMed  CAS  Google Scholar 

  • Scapin G (2002) Structural biology in drug design: selective protein kinase inhibitors. Drug Discov Today 7:601–611

    Article  PubMed  CAS  Google Scholar 

  • Seldin DC, Leder P (1995) Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle [see comments]. Science 267:894–897

    PubMed  CAS  Google Scholar 

  • Shugar D (1999) Viral and host-cell protein kinases: enticing antiviral targets and relevance of nucleoside, and viral thymidine, kinases. Pharmacol Ther 82:315–335

    Article  PubMed  CAS  Google Scholar 

  • Stahura FL, Xue L, Godden JW, Bajorath J (1999) Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases. J Mol Graph Model 17:1–9:51–52

    CAS  Google Scholar 

  • Szyszka R, Grankowski N, Felczak K, Shugar D (1995) Halogenated benzimidazoles and benzotriazoles as selective inhibitors of protein kinases CK I and CK II from Saccharomyces cerevisiae and other sources. Biochem Biophys Res Commun 208:418–424

    Article  PubMed  CAS  Google Scholar 

  • Tawfic S, Yu S, Wang H, Faust R, Davis A, Ahmed K (2001) Protein kinase CK2 signal in neoplasia. Histol histopathol 16:573–582

    PubMed  CAS  Google Scholar 

  • Toledo LM, Lydon NB, Elbaum D (1999) The structure-based design of ATP-site directed protein kinase inhibitors. Curr Med Chem 6:775–805

    PubMed  CAS  Google Scholar 

  • Traxler P, Bold G, Buchdunger E, Caravatti G, Furet P, Manley P, O’Reilly T, Wood J, Zimmermann J (2001) Tyrosine kinase inhibitors: from rational design to clinical trials. Med Res Rev 21:499–512

    Article  PubMed  CAS  Google Scholar 

  • Vangrevelinghe E, Zimmermann K, Schoepfer J, Portmann R, Fabbro D, Furet P (2003) Discovery of a potent and selective protein kinase CK2 inhibitor by high-throughput docking. J Med Chem 46:2656–2662

    Article  PubMed  CAS  Google Scholar 

  • Yim H, Lee YH, Lee CH, Lee SK (1999) Emodin, an anthraquinone derivative isolated from the rhizomes of Rheum palmatum, selectively inhibits the activity of casein kinase II as a competitive inhibitor. Planta Med 65:9–13

    Article  PubMed  CAS  Google Scholar 

  • Young TA, Delagoutte B, Endrizzi JA, Falick AM, Alber T (2003) Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser/Thr protein kinases. Nat Struct Biol 10:168–174

    Article  PubMed  CAS  Google Scholar 

  • Zandomeni R, Zandomeni MC, Shugar D, Weinmann R (1986) Casein kinase type II is involved in the inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole of specific RNA polymerase II transcription. J Biol Chem 261:3414–3419

    PubMed  CAS  Google Scholar 

  • Zhang L, Lau YK, Xi L, Hong RL, Kim DS, Chen CF, Hortobagyi GN, Chang C, Hung MC (1998) Tyrosine kinase inhibitors, emodin and its derivative repress HER-2/neuinduced cellular transformation and metastasis-associated properties. Oncogene 16:2855–2863

    Google Scholar 

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Authors and Affiliations

  1. Chemistry Department, University of Padova, Venetian Institute of Molecular Medicine (VIMM), Padova, Italy

    R. Battistutta & G. Zanotti

  2. Biological Chemistry Department, University of Padova, Venetian Institute of Molecular Medicine (VIMM), Padova, Italy

    S. Sarno

Authors
  1. R. Battistutta
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  2. S. Sarno
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  3. G. Zanotti
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Editor information

Editors and Affiliations

  1. Dipartimento di Chimica Biologica, Università di Padova, Via Trieste 75, Padova, 35121, Italy

    Lorenzo A. Pinna

  2. MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dow St., Dundee, DD1 5EH, Scotland, UK

    Patricia T.W. Cohen Ph.D. (Professor of Molecular Biology) (Professor of Molecular Biology)

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© 2005 Springer-Verlag

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Battistutta, R., Sarno, S., Zanotti, G. (2005). Inhibitors of Protein Kinase CK2: Structural Aspects. In: Pinna, L.A., Cohen, P.T. (eds) Inhibitors of Protein Kinases and Protein Phosphates. Handbook of Experimental Pharmacology, vol 167. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26670-4_6

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