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First inactive conformation of CK2 alpha, the catalytic subunit of protein kinase CK2.

Raaf J, Issinger OG, Niefind K
J Mol Biol 386 1212-21 (2009)
Related entries: 1daw, 1day, 1jwh, 1lp4, 1lpu, 1lr4, 1pjk, 2pvr, 3bqc, 3c13, 3h30, 3juh

Cited: 25 times
EuropePMC logo PMID: 19361447

Abstract

The Ser/Thr kinase casein kinase 2 (CK2) is a heterotetrameric enzyme composed of two catalytic chains (CK2alpha, catalytic subunit of CK2) attached to a dimer of two noncatalytic subunits (CK2beta, noncatalytic subunit of CK2). CK2alpha belongs to the superfamily of eukaryotic protein kinases (EPKs). To function as regulatory key components, EPKs normally exist in inactive ground states and are activated only upon specific signals. Typically, this activation is accompanied by large conformational changes in helix alpha C and in the activation segment, leading to a characteristic arrangement of catalytic key elements. For CK2alpha, however, no strict physiological control of activity is known. Accordingly, CK2alpha was found so far exclusively in the characteristic conformation of active EPKs, which is, in this case, additionally stabilized by a unique intramolecular contact between the N-terminal segment on one side, and helix alpha C and the activation segment on the other side. We report here the structure of a C-terminally truncated variant of human CK2alpha in which the enzyme adopts a decidedly inactive conformation for the first time. In this CK2alpha structure, those regulatory key regions still are in their active positions. Yet the glycine-rich ATP-binding loop, which is normally part of the canonical anti-parallel beta-sheet, has collapsed into the ATP-binding site so that ATP is excluded from binding; specifically, the side chain of Arg47 occupies the ribose region of the ATP site and Tyr50, the space required by the triphospho moiety. We discuss some factors that may support or disfavor this inactive conformation, among them coordination of small molecules at a remote cavity at the CK2alpha/CK2beta interaction region and binding of a CK2beta dimer. The latter stabilizes the glycine-rich loop in the extended active conformation known from the majority of CK2alpha structures. Thus, the novel inactive conformation for the first time provides a structural basis for the stimulatory impact of CK2beta on CK2alpha.

Articles - 3fwq mentioned but not cited (7)

  1. Specific inhibition of CK2α from an anchor outside the active site. Brear P, De Fusco C, Hadje Georgiou K, Francis-Newton NJ, Stubbs CJ, Sore HF, Venkitaraman AR, Abell C, Spring DR, Hyvönen M. Chem Sci 7 6839-6845 (2016)
  2. A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066. De Fusco C, Brear P, Iegre J, Georgiou KH, Sore HF, Hyvönen M, Spring DR. Bioorg Med Chem 25 3471-3482 (2017)
  3. 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site. Bestgen B, Krimm I, Kufareva I, Kamal AAM, Seetoh WG, Abell C, Hartmann RW, Abagyan R, Cochet C, Le Borgne M, Engel M, Lomberget T. J Med Chem 62 1803-1816 (2019)
  4. The protein kinase CK2 catalytic domain from Plasmodium falciparum: crystal structure, tyrosine kinase activity and inhibition. Ruiz-Carrillo D, Lin J, El Sahili A, Wei M, Sze SK, Cheung PCF, Doerig C, Lescar J. Sci Rep 8 7365 (2018)
  5. 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action. Bestgen B, Kufareva I, Seetoh W, Abell C, Hartmann RW, Abagyan R, Le Borgne M, Filhol O, Cochet C, Lomberget T, Engel M. J Med Chem 62 1817-1836 (2019)
  6. Conformational flexibility of human casein kinase catalytic subunit explored by metadynamics. Gouron A, Milet A, Jamet H. Biophys J 106 1134-1141 (2014)
  7. Predictive functional, statistical and structural analysis of CSNK2A1 and CSNK2B variants linked to neurodevelopmental diseases. Unni P, Friend J, Weinberg J, Okur V, Hochscherf J, Dominguez I. Front Mol Biosci 9 851547 (2022)


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  2. Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures. Nakashima M, Tohyama J, Nakagawa E, Watanabe Y, Siew CG, Kwong CS, Yamoto K, Hiraide T, Fukuda T, Kaname T, Nakabayashi K, Hata K, Ogata T, Saitsu H, Matsumoto N. J Hum Genet 64 313-322 (2019)
  3. Structural and functional insights into the regulation mechanism of CK2 by IP6 and the intrinsically disordered protein Nopp140. Lee WK, Son SH, Jin BS, Na JH, Kim SY, Kim KH, Kim EE, Yu YG, Lee HH. Proc Natl Acad Sci U S A 110 19360-19365 (2013)
  4. Antitumoral activity of allosteric inhibitors of protein kinase CK2. Moucadel V, Prudent R, Sautel CF, Teillet F, Barette C, Lafanechere L, Receveur-Brechot V, Cochet C. Oncotarget 2 997-1010 (2011)
  5. Protein kinase-inhibitor database: structural variability of and inhibitor interactions with the protein kinase P-loop. Patel RY, Doerksen RJ. J Proteome Res 9 4433-4442 (2010)
  6. Cystic fibrosis transmembrane regulator fragments with the Phe508 deletion exert a dual allosteric control over the master kinase CK2. Pagano MA, Marin O, Cozza G, Sarno S, Meggio F, Treharne KJ, Mehta A, Pinna LA. Biochem J 426 19-29 (2010)
  7. Mechanism of kinase inactivation and nonbinding of FRATide to GSK3β due to K85M mutation: molecular dynamics simulation and normal mode analysis. Lu S, Jiang Y, Lv J, Zou J, Wu T. Biopolymers 95 669-681 (2011)
  8. Enzymatic activity with an incomplete catalytic spine: insights from a comparative structural analysis of human CK2α and its paralogous isoform CK2α'. Bischoff N, Raaf J, Olsen B, Bretner M, Issinger OG, Niefind K. Mol Cell Biochem 356 57-65 (2011)
  9. Structure of the Toxoplasma gondii ROP18 kinase domain reveals a second ligand binding pocket required for acute virulence. Lim D, Gold DA, Julien L, Rosowski EE, Niedelman W, Yaffe MB, Saeij JP. J Biol Chem 288 34968-34980 (2013)
  10. Effect of double mutations K214/A-E215/Q of FRATide on GSK3β: insights from molecular dynamics simulation and normal mode analysis. Lu SY, Jiang YJ, Zou JW, Wu TX. Amino Acids 43 267-277 (2012)
  11. Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model. Ao Y, Zhang J, Liu Z, Qian M, Li Y, Wu Z, Sun P, Wu J, Bei W, Wen J, Wu X, Li F, Zhou Z, Zhu WG, Liu B, Wang Z. Sci Adv 5 eaav5078 (2019)
  12. Structural and functional analysis of the flexible regions of the catalytic α-subunit of protein kinase CK2. Papinutto E, Ranchio A, Lolli G, Pinna LA, Battistutta R. J Struct Biol 177 382-391 (2012)
  13. Low-density crystal packing of human protein kinase CK2 catalytic subunit in complex with resorufin or other ligands: a tool to study the unique hinge-region plasticity of the enzyme without packing bias. Klopffleisch K, Issinger OG, Niefind K. Acta Crystallogr D Biol Crystallogr 68 883-892 (2012)
  14. Structural basis for decreased affinity of Emodin binding to Val66-mutated human CK2 alpha as determined by molecular dynamics. Zhang N, Zhong R. J Mol Model 16 771-780 (2010)
  15. Halogen Atoms in the Protein-Ligand System. Structural and Thermodynamic Studies of the Binding of Bromobenzotriazoles by the Catalytic Subunit of Human Protein Kinase CK2. Czapinska H, Winiewska-Szajewska M, Szymaniec-Rutkowska A, Piasecka A, Bochtler M, Poznański J. J Phys Chem B 125 2491-2503 (2021)
  16. Structural Hypervariability of the Two Human Protein Kinase CK2 Catalytic Subunit Paralogs Revealed by Complex Structures with a Flavonol- and a Thieno[2,3-d]pyrimidine-Based Inhibitor. Niefind K, Bischoff N, Golub AG, Bdzhola VG, Balanda AO, Prykhod'ko AO, Yarmoluk SM. Pharmaceuticals (Basel) 10 E9 (2017)
  17. De Novo CSNK2B Mutations in Five Cases of Poirier-Bienvenu Neurodevelopmental Syndrome. Yang Q, Zhang Q, Yi S, Qin Z, Shen F, Ou S, Luo J, He S. Front Neurol 13 811092 (2022)
  18. A fragment-based approach leading to the discovery of inhibitors of CK2α with a novel mechanism of action. Brear P, De Fusco C, Atkinson EL, Iegre J, Francis-Newton NJ, Venkitaraman AR, Hyvönen M, Spring DR. RSC Med Chem 13 1420-1426 (2022)


Related citations provided by authors (9)

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  9. The CK2 alpha/CK2 beta interface of human protein kinase CK2 harbors a binding pocket for small molecules.. Raaf J, Brunstein E, Issinger OG, Niefind K Chem Biol 15 111-7 (2008)

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