Crystal Structure of a C-terminal Deletion Mutant of Human Protein Kinase CK2 Catalytic Subunit

Ermakova, Inessa; Boldyreff, Brigitte; Issinger, Olaf‐Georg; Niefind, Karsten

doi:10.1016/s0022-2836(03)00638-7

Cited by 70 publications

(77 citation statements)

References 42 publications

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“…Therefore, we present here the first unbound threedimensional (3D) structure of a CK2b construct that is fully capable of CK2a recruitment and we quantify its affinity to CK2a thermodynamically. This structure supplements existing structures of unbound human CK2a (Ermakova et al 2003;Niefind et al 2007;Raaf et al 2008) and of the ''bound case,'' i.e., the human CK2 holoenzyme (Niefind et al 2001); thus, it allows a comprehensive view on the conformational changes that occur at the CK2a/CK2b interface upon association.…”

mentioning

confidence: 61%

“…In all unbound structures (Ermakova et al 2003;Niefind et al 2007;Raaf et al 2008) the just mentioned surface patch is not directly accessible for CK2b; rather the neighboring b4b5-loop occurs in a closed and CK2b incompatible conformation (see two representative examples in Fig. 1C).…”

Section: Thermodynamic Backgroundmentioning

confidence: 99%

“…First, we used differential scanning calorimetry (DSC) to determine the melting temperatures of hsCK2b , of hsCK2a 1-335 -a fully active C-terminal deletion mutant of human CK2a (Ermakova et al 2003)-and of a tetrameric complex of both. The resulting temperature scans (Fig.…”

Section: Thermodynamic Backgroundmentioning

confidence: 99%

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The interaction of CK2α and CK2β, the subunits of protein kinase CK2, requires CK2β in a preformed conformation and is enthalpically driven

et al. 2008

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The protein kinase CK2 (former name: ''casein kinase 2'') predominantly occurs as a heterotetrameric holoenzyme composed of two catalytic chains (CK2a) and two noncatalytic subunits (CK2b). The CK2b subunits form a stable dimer to which the CK2a monomers are attached independently. In contrast to the cyclins in the case of the cyclin-dependent kinases CK2b is no on-switch of CK2a; rather the formation of the CK2 holoenzyme is accompanied with an overall change of the enzyme's profile including a modulation of the substrate specificity, an increase of the thermostability, and an allocation of docking sites for membranes and other proteins. In this study we used C-terminal deletion variants of human CK2a and CK2b that were enzymologically fully competent and in particular able to form a heterotetrameric holoenzyme. With differential scanning calorimetry (DSC) we confirmed the strong thermostabilization effect of CK2a on CK2b with an upshift of the CK2a melting temperature of more than 9°. Using isothermal titration calorimetry (ITC) we measured a dissociation constant of 12.6 nM. This high affinity between CK2a and CK2b is mainly caused by enthalpic rather than entropic contributions. Finally, we determined a crystal structure of the CK2b construct to 2.8 Å resolution and revealed by structural comparisons with the CK2 holoenzyme structure that the CK2b conformation is largely conserved upon association with CK2a, whereas the latter undergoes significant structural adaptations of its backbone.

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confidence: 61%

Section: Thermodynamic Backgroundmentioning

confidence: 99%

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The interaction of CK2α and CK2β, the subunits of protein kinase CK2, requires CK2β in a preformed conformation and is enthalpically driven

et al. 2008

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“…The purity of the CK2 holoenzyme was superior to 99% (Fig. 6) [41]. For initial testing, inhibition was determined relative to the controls at inhibitor concentrations of 10 mM in DMSO as the solvent.…”

Section: Inhibition Of Human Ck2 Holoenzymementioning

confidence: 99%

“…The band below the CK2a belongs to the well-known degradation product of the a-subunit CK2a (amino acids 1e335), which is supposed to be enzymatically active and usually occurs during purification [41]. Initially, a CK2/CX-4945 MD simulation was carried out as control trajectory, finding that both global complex conformation and polar proteineinhibitor interactions observed in the crystal structure resulted stable during the simulation time scale.…”

Section: Molecular Dynamics Of Ck2 Complexesmentioning

confidence: 99%

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Guillon¹,

Borgne²,

Rimbault³

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tHerein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxalinecarboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC 50 in the microand sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl) amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC 50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors.

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Structural Bases of Protein Kinase CK2 Function and Inhibition

Niefind

Battistutta

2013

Protein Kinase CK2

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Crystal Structure of a C-terminal Deletion Mutant of Human Protein Kinase CK2 Catalytic Subunit

Cited by 70 publications

References 42 publications

The interaction of CK2α and CK2β, the subunits of protein kinase CK2, requires CK2β in a preformed conformation and is enthalpically driven

The interaction of CK2α and CK2β, the subunits of protein kinase CK2, requires CK2β in a preformed conformation and is enthalpically driven

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

Structural Bases of Protein Kinase CK2 Function and Inhibition

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