Universität zu Köln

Guerra, Barbara ORCID: 0000-0003-1136-2413, Bischoff, Nils, Bdzhola, Volodymyr G., Yarmoluk, Sergiy M., Issinger, Olaf-Georg, Golub, Andriy G. and Niefind, Karsten ORCID: 0000-0002-0183-6315 (2015). A Note of Caution on the Role of Halogen Bonds for Protein Kinase/Inhibitor Recognition Suggested by High- And Low-Salt CK2 alpha Complex Structures. ACS Chem. Biol., 10 (7). S. 1654 - 1661. WASHINGTON: AMER CHEMICAL SOC. ISSN 1554-8937

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Abstract

CK2 is a Ser/Thr kinase recruited by tumor cells to avoid cell death. 4'-Carboxy-6,8-dibromo-flavonol (FLC26) is a nanomolar CK2 inhibitor reducing the physiological phosphorylation of CK2 biomarkers and inducing cell death. Its binding mode to the ATP site was predicted to depend primarily on noncovalent interactions not comprising halogen bonds. We confirm this by two independent cocrystal structures which additionally show that FLC26 is selective for an open, protein kinase-untypical conformation of the hinge/helix alpha D region. The structures suggest how the bromo substituents, found previously in lead optimization studies, contribute to the inhibitory efficacy. In this context, one of the complex structures, obtained by crystallization with the kosmotropic salt NaCl, revealed an unconventional pi-halogen bond between the 8-bromo substituent of FLC26 and an aromatic side chain which is absent under low-salt conditions. The kosmotropic salt sensitivity of pi-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Guerra, Barbara UNSPECIFIED orcid.org/0000-0003-1136-2413 UNSPECIFIED Bischoff, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Bdzhola, Volodymyr G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yarmoluk, Sergiy M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Issinger, Olaf-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Golub, Andriy G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niefind, Karsten UNSPECIFIED orcid.org/0000-0002-0183-6315 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-399445
DOI:	10.1021/acschembio.5b00235
Journal or Publication Title:	ACS Chem. Biol.
Volume:	10
Number:	7
Page Range:	S. 1654 - 1661
Date:	2015
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1554-8937
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CK2 CATALYTIC SUBUNIT; KINASE CK2; SELECTIVE INHIBITOR; CRYSTAL-STRUCTURE; BENZIMIDAZOLE; PLASTICITY; DESIGN Multiple languages Biochemistry & Molecular Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/39944