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Pharmaceuticals 2017, 10(1), 9; doi:10.3390/ph10010009

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

1
Department für Chemie, Institut für Biochemie, Universität zu Köln, Otto-Fischer-Straße 12–14, D-50674 Köln, Germany
2
Otava Ltd., 400 Applewood Crescent, Unit 100, Vaughan, ON L4K 0C3, Canada
3
Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine
This publication is dedicated to Professor Dr. Olaf-Georg Issinger on the occasion of his 70th birthday.
*
Author to whom correspondence should be addressed.
Academic Editor: Mathias Montenarh
Received: 1 December 2016 / Revised: 3 January 2017 / Accepted: 5 January 2017 / Published: 11 January 2017
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Abstract

Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog CK2α′ in complex with two ATP-competitive inhibitors—based on either a flavonol or a thieno[2,3-d]pyrimidine framework—are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix αD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2α and CK2α′. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations. View Full-Text
Keywords: protein kinase CK2; casein kinase 2; ATP-competitive inhibitors; halogen bond protein kinase CK2; casein kinase 2; ATP-competitive inhibitors; halogen bond
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Niefind, K.; Bischoff, N.; Golub, A.G.; Bdzhola, V.G.; Balanda, A.O.; Prykhod’ko, A.O.; Yarmoluk, S.M. 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. Pharmaceuticals 2017, 10, 9.

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