Universität zu Köln

Lindenblatt, Dirk ORCID: 0000-0002-5561-1082, Nickelsen, Anna, Applegate, Violetta M., Hochscherf, Jennifer, Witulski, Benedict, Bouaziz, Zouhair, Marminon, Christelle ORCID: 0000-0002-4043-3949, Bretner, Maria, Le Borgne, Marc ORCID: 0000-0003-1398-075X, Jose, Joachim and Niefind, Karsten ORCID: 0000-0002-0183-6315 (2019). Diacritic Binding of an Indenoindole Inhibitor by CK2 alpha Paralogs Explored by a Reliable Path to Atomic Resolution CK2 alpha ' Structures. ACS Omega, 4 (3). S. 5471 - 5479. WASHINGTON: AMER CHEMICAL SOC. ISSN 2470-1343

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Abstract

CK2 alpha and CK2 alpha' are the two isoforms of the catalytic subunit of human protein kinase CK2, an important target for cancer therapy. They have similar, albeit not identical functional and structural properties, and were occasionally reported to be inhibited with distinct efficacies by certain ATP-competitive ligands. Here, we present THN27, an indeno[1,2-b] indole derivative, as a further inhibitor with basal isoform selectivity. The selectivity disappears when measured using CK2 alpha/CK2 alpha' complexes with CK2 beta, the regulatory CK2 subunit. Co-crystal structures of THN27 with CK2 alpha and CK2 alpha' reveal that subtle differences in the conformational variability of the inter-domain hinge region are correlated with the observed effect. In the case of CK2 alpha', a crystallographically problematic protein so far, this comparative structural analysis required the development of an experimental strategy that finally enables atomic resolution structure determinations with ab initio phasing of potentially any ATP-competitive CK2 inhibitor and possibly many non-ATP-competitive ligands as well bound to CK2 alpha'.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lindenblatt, Dirk UNSPECIFIED orcid.org/0000-0002-5561-1082 UNSPECIFIED Nickelsen, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Applegate, Violetta M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hochscherf, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Witulski, Benedict UNSPECIFIED UNSPECIFIED UNSPECIFIED Bouaziz, Zouhair UNSPECIFIED UNSPECIFIED UNSPECIFIED Marminon, Christelle UNSPECIFIED orcid.org/0000-0002-4043-3949 UNSPECIFIED Bretner, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Le Borgne, Marc UNSPECIFIED orcid.org/0000-0003-1398-075X UNSPECIFIED Jose, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Niefind, Karsten UNSPECIFIED orcid.org/0000-0002-0183-6315 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-154834
DOI:	10.1021/acsomega.8b03415
Journal or Publication Title:	ACS Omega
Volume:	4
Number:	3
Page Range:	S. 5471 - 5479
Date:	2019
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	2470-1343
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 PROTEIN-KINASE CK2; CATALYTIC-SUBUNIT; CRYSTAL-STRUCTURE; POTENT; SITE; ATP; PLASTICITY; COMPLEX Multiple languages Chemistry, Multidisciplinary Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15483