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:
CreatorsEmailORCIDORCID Put Code
Lindenblatt, DirkUNSPECIFIEDorcid.org/0000-0002-5561-1082UNSPECIFIED
Nickelsen, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Applegate, Violetta M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hochscherf, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witulski, BenedictUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouaziz, ZouhairUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marminon, ChristelleUNSPECIFIEDorcid.org/0000-0002-4043-3949UNSPECIFIED
Bretner, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Le Borgne, MarcUNSPECIFIEDorcid.org/0000-0003-1398-075XUNSPECIFIED
Jose, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niefind, KarstenUNSPECIFIEDorcid.org/0000-0002-0183-6315UNSPECIFIED
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: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN-KINASE CK2; CATALYTIC-SUBUNIT; CRYSTAL-STRUCTURE; POTENT; SITE; ATP; PLASTICITY; COMPLEXMultiple languages
Chemistry, MultidisciplinaryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15483

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