Structural Bases of Protein Kinase CK2 Function and Inhibition

Niefind, Karsten; Battistutta, Roberto

doi:10.1002/9781118482490.ch1

Cited by 11 publications

(18 citation statements)

References 223 publications

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“…It is complementary to an ATP-site which is—compared to other EPKs—rather narrow and hydrophobic due to some bulky and non-polar side chains located at both flanking domains [ 40 ]. However, with respect to the peripheral derivatization with halogens, charged and aromatic groups and hydrogen bond donors/acceptors a fairly broad variety of substituents was found in the past [ 41 ]. Many CK2 inhibitors—among them CX-4945 (silmitasertib) [ 42 ] which acquired the state of a “benchmark” inhibitor in recent years—form electrostatic interactions with a positively charged area near Lys68 [ 43 ] and π-π-interactions with Phe113 [ 44 ], CK2α′s equivalent of the critical “gatekeeper” residue of EPKs [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, an important anchor region for hydrogen/halogen bonds is the peptide backbone of the interdomain hinge. Emodin and other examples have shown that CK2 inhibitors do not necessarily require these hinge interactions for binding [ 46 ], but to achieve affinities in the low nanomolar range they are regarded as imperative [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′

et al. 2017

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Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-b]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-b]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-b]indole-based CK2 inhibitor described yet (IC50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (4p). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2α and CK2α′, the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2α/CK2α′, but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydrogen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2α structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix αD region conformation and of the salt content in the crystallization medium.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′

et al. 2017

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“…Furthermore, some ligands forming a covalent bond with the kinase-specific nucleophilic residue located within the ATP-binding pocket have been developed (Liu et al, 2013). Other options to improve selectivity include non-ATP-competitive inhibitors (Harrison et al, 2008;Battistutta, 2009;Kirkland & McInnes, 2009;Garuti et al, 2010), such as allosteric ones (Bogoyevitch & Fairlie, 2007;Lamba & Ghosh, 2012;Cowan-Jacob et al, 2014), some of which preferably bind to the "DFGout" conformation of a kinase, stabilizing its inactive conformation (Dietrich et al, 2010;Zhao et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Halogen bonds involved in binding of halogenated ligands by protein kinases.

et al. 2016

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Analysis of 664 known structures of protein kinase complexes with halogenated ligands revealed 424 short contacts between a halogen atom and a potential protein X-bond acceptor, the topology and geometry of which were analyzed according to the type of a halogen atom (X = Cl, Br, I) and a putative protein X-bond acceptor. Among 236 identified halogen bonds, the most represented ones are directed to backbone carbonyls of the hinge region and may replace the pattern of ATP-like hydrogen bonds. Some halogen-π interactions with either aromatic residues or peptide bonds, that accompany the interaction with the hinge region, may possibly enhance ligand selectivity. Interestingly, many of these halogen-π interactions are bifurcated. Geometrical preferences identify iodine as the strongest X-bond donor, less so bromine, while virtually no such preferences were observed for chlorine; and a backbone carbonyl as the strongest X-bond acceptor. The presence of a halogen atom in a ligand additionally affects the properties of proximal hydrogen bonds, which according to geometrical parameters get strengthened, when a nitrogen of a halogenated ligand acts as the hydrogen bond donor.

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“…This result suggests that CK2 somehow inhibits PERK signalling but the mechanism of PERK inhibition by CK2 is still an enigma. In the same study it was shown that CK2 inhibition with K27, which is a derivative of the commonly used inhibitor TBB [29], leads to an increase in serine 51 phosphorylation of eIF2α. This increase in the phosphorylation of eIF2α was also shown in another study using HeLa cells and TBB [30] or quinalizarin [31] as CK2 inhibitors [32].…”

Section: The Perk Mediated Pathwaymentioning

confidence: 94%

Protein kinase CK2 in the ER stress response

Götz¹,

Montenarh²

2013

ABC

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The endoplasmic reticulum is the central organelle within a eukaryotic cell where newly synthesized proteins are processed and properly folded. An excess of unfolded or mis-folded proteins induces ER stress signalling pathways. Usually this means a pro-survival strategy for the cell, whereas under extended stress conditions the ER stress signalling pathways have a pro-apoptotic function. CK2 plays a key role in the regulation of the pro-survival as well as the proapoptotic ER stress signalling by directly modulating the activities of members of the ER stress signalling pathways by phosphorylation, regulating the expression of the key factors of the signalling pathways or binding to regulator proteins. The present review will summarize the state of the art in this new emerging field.

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Structural Bases of Protein Kinase CK2 Function and Inhibition

Cited by 11 publications

References 223 publications

Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′

Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′

Halogen bonds involved in binding of halogenated ligands by protein kinases.

Protein kinase CK2 in the ER stress response

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