5n9l

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==Crystal structure of human Protein kinase CK2 catalytic subunit in complex with the ATP-competitive dibenzofuran inhibitor TF (4b)==
==Crystal structure of human Protein kinase CK2 catalytic subunit in complex with the ATP-competitive dibenzofuran inhibitor TF (4b)==
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<StructureSection load='5n9l' size='340' side='right' caption='[[5n9l]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
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<StructureSection load='5n9l' size='340' side='right'caption='[[5n9l]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5n9l]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N9L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5N9L FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5n9l]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N9L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5N9L FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8QH:(4~{Z})-6,7-bis(chloranyl)-4-[[(4-methylphenyl)amino]methylidene]-8-oxidanyl-1,2-dihydrodibenzofuran-3-one'>8QH</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5n9n|5n9n]], [[5n9k|5n9k]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8QH:(4~{Z})-6,7-bis(chloranyl)-4-[[(4-methylphenyl)amino]methylidene]-8-oxidanyl-1,2-dihydrodibenzofuran-3-one'>8QH</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5n9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n9l OCA], [https://pdbe.org/5n9l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5n9l RCSB], [https://www.ebi.ac.uk/pdbsum/5n9l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5n9l ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5n9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n9l OCA], [http://pdbe.org/5n9l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5n9l RCSB], [http://www.ebi.ac.uk/pdbsum/5n9l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5n9l ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/CSK21_HUMAN CSK21_HUMAN]] Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.<ref>PMID:11239457</ref> <ref>PMID:11704824</ref> <ref>PMID:16193064</ref> <ref>PMID:19188443</ref>
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[https://www.uniprot.org/uniprot/CSK21_HUMAN CSK21_HUMAN] Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.<ref>PMID:11239457</ref> <ref>PMID:11704824</ref> <ref>PMID:16193064</ref> <ref>PMID:19188443</ref>
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<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Protein kinase CK2 (formerly called: casein kinase 2) is a heterotetrameric enzyme composed of two separate catalytic chains (CK2alpha) and a stable dimer of two non-catalytic subunits (CK2beta). CK2alpha is a highly conserved member of the superfamily of eukaryotic protein kinases. The crystal structure of a C-terminal deletion mutant of human CK2alpha was solved and refined to 2.5A resolution. In the crystal the CK2alpha mutant exists as a monomer in agreement with the organization of the subunits in the CK2 holoenzyme. The refined structure shows the helix alphaC and the activation segment, two main regions of conformational plasticity and regulatory importance in eukaryotic protein kinases, in active conformations stabilized by extensive contacts to the N-terminal segment. This arrangement is in accordance with the constitutive activity of the enzyme. By structural superimposition of human CK2alpha in isolated form and embedded in the human CK2 holoenzyme the loop connecting the strands beta4 and beta5 and the ATP-binding loop were identified as elements of structural variability. This structural comparison suggests that the ATP-binding loop may be the key region by which the non-catalytic CK2beta dimer modulates the activity of CK2alpha. The beta4/beta5 loop was found in a closed conformation in contrast to the open conformation observed for the CK2alpha subunits of the CK2 holoenzyme. CK2alpha monomers with this closed beta4/beta5 loop conformation are unable to bind CK2beta dimers in the common way for sterical reasons, suggesting a mechanism to protect CK2alpha from integration into CK2 holoenzyme complexes. This observation is consistent with the growing evidence that CK2alpha monomers and CK2beta dimers can exist in vivo independently from the CK2 holoenzyme and may possess physiological roles of their own.
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Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b, d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC50 values of 7 nM (4a) and 5 nM (5) and an apparent Ki value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected pi-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency.
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Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit.,Ermakova I, Boldyreff B, Issinger OG, Niefind K J Mol Biol. 2003 Jul 25;330(5):925-34. PMID:12860116<ref>PMID:12860116</ref>
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A pi-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors.,Schnitzler A, Gratz A, Bollacke A, Weyrich M, Kucklander U, Wunsch B, Gotz C, Niefind K, Jose J Pharmaceuticals (Basel). 2018 Feb 17;11(1). pii: ph11010023. doi:, 10.3390/ph11010023. PMID:29462988<ref>PMID:29462988</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
<div class="pdbe-citations 5n9l" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 5n9l" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Casein kinase 3D structures|Casein kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Homo sapiens]]
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[[Category: Bollacke, A]]
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[[Category: Large Structures]]
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[[Category: Goetz, C]]
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[[Category: Bollacke A]]
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[[Category: Gratz, A]]
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[[Category: Goetz C]]
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[[Category: Jose, J]]
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[[Category: Gratz A]]
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[[Category: Kucklaender, U]]
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[[Category: Jose J]]
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[[Category: Niefind, K]]
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[[Category: Kucklaender U]]
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[[Category: Schnitzler, A]]
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[[Category: Niefind K]]
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[[Category: Weyrich, M]]
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[[Category: Schnitzler A]]
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[[Category: Wuensch, B]]
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[[Category: Weyrich M]]
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[[Category: Atp-competitive inhititor]]
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[[Category: Wuensch B]]
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[[Category: Casein kinase 2]]
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[[Category: Ck2]]
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[[Category: Dibenzofuran derivative]]
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[[Category: Protein kinase]]
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[[Category: Protein phosphorylation]]
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[[Category: Tight-binding inhibitor]]
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[[Category: Transferase]]
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Current revision

Crystal structure of human Protein kinase CK2 catalytic subunit in complex with the ATP-competitive dibenzofuran inhibitor TF (4b)

PDB ID 5n9l

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