Development of a Potent and Selective Chemical Probe for the Pleiotropic Kinase CK2

Wells, Carrow; Drewry, David H.; Pickett, Julie E.; Tjaden, Amelie; Krämer, Andreas; Müller, Susanne; Gyenis, Laszlo; Menyhart, Daniel; Litchfield, David W.; Knapp, S.; Axtman, Alison D.

doi:10.2139/ssrn.3732376

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“…Surprisingly, there were no water molecules near Trp176 and Glu81, which are found in the co-crystal structures of most reported CK2-inhibitor complexes. [19][20][21][22][23] For example, Fig. 2 shows the co-crystal structure of CX-4945 with CK2α (PDBID: 3PE1) superimposed on that of 1 with CK2α (PDB ID: 7BU4) and aligned for comparison.…”

Section: Introductionmentioning

confidence: 99%

Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water

Nishiwaki,

Nakatani,

Nakamura

et al. 2024

RSC Med. Chem.

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Section: Introductionmentioning

confidence: 99%

Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water

Nishiwaki,

Nakatani,

Nakamura

et al. 2024

RSC Med. Chem.

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Discovery and Exploration of Protein Kinase CK2 Binding Sites Using CK2α′Cys336Ser as an Exquisite Crystallographic Tool

Werner,

Lindenblatt,

Viht

et al. 2023

Kinases and Phosphatases

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The structural knowledge about protein kinase CK2 is dominated by crystal structures of human CK2α, the catalytic subunit of human CK2, and the product of the CSNK2A1 gene. In contrast, far fewer structures of CK2α′, its paralogous isoform and the product of the CSNK2A2 gene, have been published. However, according to a PDB survey, CK2α′ is the superior alternative for crystallographic studies because of the inherent potential of the single mutant CK2α′Cys336Ser to provide crystal structures with atomic resolution. In particular, a triclinic crystal form of CK2α′Cys336Ser is a robust tool to determine high-quality enzyme-ligand complex structures via soaking. In this work, further high-resolution CK2α′Cys336Ser structures in complex with selected ligands emphasizing this trend are described. In one of these structures, the “N-terminal segment site”, a small-molecule binding region never found in any eukaryotic protein kinase and holding the potential for the development of highly selective substrate-competitive CK2 inhibitors, was discovered. In order to also address the binding site for the non-catalytic subunit CK2β, which is inaccessible in these triclinic CK2α′Cys336Ser crystals for small molecules, a reliable path to a promising monoclinic crystal form of CK2α′Cys336Ser is presented. In summary, the quality of CK2α′Cys336Ser as an exquisite crystallographic tool is solidified.

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Development of a Potent and Selective Chemical Probe for the Pleiotropic Kinase CK2

Cited by 2 publications

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Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water

Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water

Discovery and Exploration of Protein Kinase CK2 Binding Sites Using CK2α′Cys336Ser as an Exquisite Crystallographic Tool

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