Structure of the Human Protein Kinase CK2 Catalytic Subunit CK2α′ and Interaction Thermodynamics with the Regulatory Subunit CK2β

Bischoff, N.; Olsen, Birgitte Brinkmann; Raaf, Jennifer; Bretner, Maria; Issinger, Olaf‐Georg; Niefind, Karsten

doi:10.1016/j.jmb.2011.01.020

Cited by 43 publications

(60 citation statements)

References 52 publications

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“…Elucidation of the crystal structure revealed that the holoenzyme consists of two catalytic a-subunits and a 'regulatory' b-subunit dimer, forming a heterotetramer [7]. The crystal structure of the CK2a subunit [8] and its paralogue, CK2a 0 , have been solved [9,10] together with the CK2 holoenzyme [7] consisting of 2a and 2b subunits. The CK2b dimer confers stability, and enhances enzyme activity [11].…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library

Guerra

Hochscherf²,

Jensen³

et al. 2015

Mol Cell Biochem

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The anti-apoptotic protein kinase CK2 increasingly becomes an attractive target in cancer research with great therapeutic potential. Here, we have performed an in vitro screening of the Diversity Set III of the DTP program from the NCI/NIH, comprising 1600 compounds. We have identified 1,3-Dichloro-6-[(E)-((4-methoxyphenyl)imino)methyl] dibenzo(b,d) furan-2,7-diol (referred to as D11) to be a potent and selective inhibitor of protein kinase CK2. The D11 compound was tested against 354 eukaryotic protein kinases. By setting the threshold for inhibition to <2% remaining kinase activity, only DYRK1B, IRAK1 and PIM3 were inhibited to an extent as the tetrameric CK2 holoenzyme and its catalytic subunits α and α'. The IC50 values for the CK2α and CK2α' were on average 1-2 nM in comparison to the DYRK1B, IRAK1 and PIM3 kinases, which ranged from 18 to 49 nM. Cell permeability and efficacy of D11 were tested with cells in culture. In MIA PaCa-2 cells (human pancreatic carcinoma cell line), the phosphorylation of the CK2 biomarker CDC37 at S13 was almost completely inhibited in the presence of D11. This was observed both under normoxia and hypoxia. In the case of the human non-small cell lung carcinoma cell line, H1299, increasing amounts of D11 led to an inhibition of S380/T382/383 phosphorylation in PTEN, another biomarker for CK2 activity.

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Section: Introductionmentioning

confidence: 99%

Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library

Guerra

Hochscherf²,

Jensen³

et al. 2015

Mol Cell Biochem

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“…Although CK2 and CK2Ј share remarkable sequence and structural similarity throughout most of the proteins (Bischoff et al, 2011;Lozeman et al, 1990), they have completely divergent C-termini, meaning that CK2Ј does not contain the four mitotic phosphorylation sites present in CK2. Previous work on CK2 localization has produced mixed results as to whether CK2 alone or both catalytic subunits can localize to the mitotic spindle (Krek et al, 1992;Yu et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Localization of phosphorylated CK2α to the mitotic spindle requires the peptidyl-prolyl isomerase Pin1

St‐Denis

Bailey

Parker

et al. 2011

Journal of Cell Science

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SummaryCK2 is a serine/threonine kinase with many substrates, largely unknown modes of regulation and essential roles in mitotic progression. CK2, a catalytic subunit of CK2, is phosphorylated in mitosis, and here we examine the effect of phosphorylation on CK2 localization. Using phosphospecific antibodies, we show that CK2 localizes to the mitotic spindle in a phosphorylation-dependent manner. Mitotic spindle localization requires the unique C-terminus of CK2, and involves a novel regulatory mechanism in which phosphorylation of CK2 facilitates binding to the peptidyl-prolyl isomerase Pin1, which is required for CK2 mitotic spindle localization. This could explain how the constitutive activity of CK2 might be targeted towards mitotic substrates. Furthermore, because Pin1 has many important spindle substrates, this might represent a general mechanism for localization of mitotic signalling proteins.

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“…1 2.4.6. General procedure for preparation of racemic acetates (9)(10)(11) To a solution of racemic alcohol (0.2 mmol), DCC (45.4 mg, 0.22 mmol) and catalytic amount of DMAP in dichloromethane (10 mL), glacial acetic acid (12.6 mg, 0.22 mmol) was added and the mixture was stirred overnight at r.t. Then the mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography (99:1, dichloromethane/methanol) giving pure product as white crystals.…”

Section: -(4567-tetrabromo-2h-benzotriazol-2-yl)butan-2-ol (5)mentioning

confidence: 99%

“…However, only a small number of those compounds have shown higher activity against CK2␣ subunit: among them 3-(4,5,6,7-tetrabromo-1H-benzotriazol-1-yl)-propan-1-ol and its 2H isomer have shown IC 50 about 0.33 M. Crystallographic data of the complex with CK2␣ subunit has proven that a hydrogen bond between the hydroxyl group and Asp176 and Lys68 exists [9]. This result has shown that designing new TBBt derivatives with a polar functional group in a side chain is still reasonable.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new optically pure tetrabromobenzotriazole derivatives via lipase-catalyzed transesterification

Wawro

Wielechowska

Bretner

2013

Journal of Molecular Catalysis B: Enzymatic

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Structure of the Human Protein Kinase CK2 Catalytic Subunit CK2α′ and Interaction Thermodynamics with the Regulatory Subunit CK2β

Cited by 43 publications

References 52 publications

Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library

Identification of a novel potent, selective and cell permeable inhibitor of protein kinase CK2 from the NIH/NCI Diversity Set Library

Localization of phosphorylated CK2α to the mitotic spindle requires the peptidyl-prolyl isomerase Pin1

Synthesis of new optically pure tetrabromobenzotriazole derivatives via lipase-catalyzed transesterification

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