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5ONI

LOW-SALT STRUCTURE OF PROTEIN KINASE CK2 CATALYTIC SUBUNIT (ISOFORM CK2ALPHA) IN COMPLEX WITH THE INDENOINDOLE-TYPE INHIBITOR 4P

Summary for 5ONI
Entry DOI10.2210/pdb5oni/pdb
Related5OMY
DescriptorCasein kinase II subunit alpha, 4-(3-methylbut-2-enoxy)-5-propan-2-yl-7,8-dihydro-6~{H}-indeno[1,2-b]indole-9,10-dione, SULFATE ION, ... (7 entities in total)
Functional Keywordsprotein kinase ck2, casein kinase 2, indenoindole-type inhibitors, transferase
Biological sourceHomo sapiens (Human)
Cellular locationNucleus : P68400
Total number of polymer chains2
Total formula weight92288.67
Authors
Hochscherf, J.,Lindenblatt, D.,Witulski, B.,Birus, R.,Aichele, D.,Marminon, C.,Bouaziz, Z.,Le Borgne, M.,Jose, J.,Niefind, K. (deposition date: 2017-08-03, release date: 2017-12-27, Last modification date: 2024-01-17)
Primary citationHochscherf, J.,Lindenblatt, D.,Witulski, B.,Birus, R.,Aichele, D.,Marminon, C.,Bouaziz, Z.,Le Borgne, M.,Jose, J.,Niefind, K.
Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2 alpha and Its Paralog CK2 alpha '.
Pharmaceuticals (Basel), 10:-, 2017
Cited by
PubMed Abstract: Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-]indole-based CK2 inhibitor described yet (IC = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2-]indole-9,10-dione (). Herein, we demonstrate the membrane permeability of and describe co-crystal structures of with CK2α and CK2α', the paralogs of human CK2 catalytic subunit. As expected, occupies the narrow, hydrophobic ATP site of CK2α/CK2α', but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydro-gen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2α structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix αD region conformation and of the salt content in the crystallization medium.
PubMed: 29236079
DOI: 10.3390/ph10040098
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2 Å)
Structure validation

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