title: 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.
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.
authors.affiliation: Department für Chemie, Institut für Biochemie, Universität zu Köln, Otto-Fischer-Straße 12-14, D-50674 Köln, Germany. Karsten.Niefind@uni-koeln.de.
authors.forename: Karsten
authors.initials: K
authors.lastname: Niefind
authors.affiliation: Department für Chemie, Institut für Biochemie, Universität zu Köln, Otto-Fischer-Straße 12-14, D-50674 Köln, Germany. nils.bischoff@outlook.com.
authors.forename: Nils
authors.initials: N
authors.lastname: Bischoff
authors.affiliation: Otava Ltd., 400 Applewood Crescent, Unit 100, Vaughan, ON L4K 0C3, Canada. andrew.golub@gmail.com.
authors.forename: Andriy G
authors.initials: AG
authors.lastname: Golub
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine. volodymyr_bdzhola@ukr.net.
authors.forename: Volodymyr G
authors.initials: VG
authors.lastname: Bdzhola
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine. b.anatolij@gmail.com.
authors.forename: Anatoliy O
authors.initials: AO
authors.lastname: Balanda
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine. a.o.prykhodko@gmail.com.
authors.forename: Andriy O
authors.initials: AO
authors.lastname: Prykhod'ko
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine. yarmolyuksm@gmail.com.
authors.forename: Sergiy M
authors.initials: SM
authors.lastname: Yarmoluk
keywords: ATP-competitive inhibitors; casein kinase 2; halogen bond; protein kinase CK2