5ONI
LOW-SALT STRUCTURE OF PROTEIN KINASE CK2 CATALYTIC SUBUNIT (ISOFORM CK2ALPHA) IN COMPLEX WITH THE INDENOINDOLE-TYPE INHIBITOR 4P
Summary for 5ONI
Entry DOI | 10.2210/pdb5oni/pdb |
Related | 5OMY |
Descriptor | Casein 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 Keywords | protein kinase ck2, casein kinase 2, indenoindole-type inhibitors, transferase |
Biological source | Homo sapiens (Human) |
Cellular location | Nucleus : P68400 |
Total number of polymer chains | 2 |
Total formula weight | 92288.67 |
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 citation | Hochscherf, 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: 29236079DOI: 10.3390/ph10040098 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
Download full validation report