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| | <StructureSection load='6hmc' size='340' side='right'caption='[[6hmc]], [[Resolution|resolution]] 1.03Å' scene=''> | | <StructureSection load='6hmc' size='340' side='right'caption='[[6hmc]], [[Resolution|resolution]] 1.03Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6hmc]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HMC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HMC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6hmc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HMC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HMC FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FXB:5-propan-2-yl-4-prop-2-enoxy-7,8-dihydro-6~{H}-indeno[1,2-b]indole-9,10-dione'>FXB</scene></td></tr> | | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FXB:5-propan-2-yl-4-prop-2-enoxy-7,8-dihydro-6~{H}-indeno[1,2-b]indole-9,10-dione'>FXB</scene></td></tr> |
| | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CSNK2A2, CK2A2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| | <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> | | <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> |
| | <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=6hmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hmc OCA], [http://pdbe.org/6hmc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hmc RCSB], [http://www.ebi.ac.uk/pdbsum/6hmc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hmc ProSAT]</span></td></tr> | | <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=6hmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hmc OCA], [http://pdbe.org/6hmc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hmc RCSB], [http://www.ebi.ac.uk/pdbsum/6hmc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hmc ProSAT]</span></td></tr> |
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| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | 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-b]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-b]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-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-b]indole-based CK2 inhibitor described yet (IC50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10 -dione (4p). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2alpha and CK2alpha', the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2alpha/CK2alpha', 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 CK2alpha structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix alphaD region conformation and of the salt content in the crystallization medium.
| + | CK2alpha and CK2alpha' 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 CK2alpha/CK2alpha' complexes with CK2beta, the regulatory CK2 subunit. Co-crystal structures of THN27 with CK2alpha and CK2alpha' reveal that subtle differences in the conformational variability of the interdomain hinge region are correlated with the observed effect. In the case of CK2alpha', 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 CK2alpha'. |
| | | | |
| - | 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 CK2alpha and Its Paralog CK2alpha'.,Hochscherf J, Lindenblatt D, Witulski B, Birus R, Aichele D, Marminon C, Bouaziz Z, Le Borgne M, Jose J, Niefind K Pharmaceuticals (Basel). 2017 Dec 13;10(4). pii: ph10040098. doi:, 10.3390/ph10040098. PMID:29236079<ref>PMID:29236079</ref>
| + | Diacritic Binding of an Indenoindole Inhibitor by CK2alpha Paralogs Explored by a Reliable Path to Atomic Resolution CK2alpha' Structures.,Lindenblatt D, Nickelsen A, Applegate VM, Hochscherf J, Witulski B, Bouaziz Z, Marminon C, Bretner M, Le Borgne M, Jose J, Niefind K ACS Omega. 2019 Mar 19;4(3):5471-5478. doi: 10.1021/acsomega.8b03415. eCollection, 2019 Mar 31. PMID:31559376<ref>PMID:31559376</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | <div class="pdbe-citations 6hmc" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6hmc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Casein kinase 3D structures|Casein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Human]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| | [[Category: Non-specific serine/threonine protein kinase]] | | [[Category: Non-specific serine/threonine protein kinase]] |
| Structural highlights
Function
[CSK22_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.[1] [2] [3]
Publication Abstract from PubMed
CK2alpha and CK2alpha' 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 CK2alpha/CK2alpha' complexes with CK2beta, the regulatory CK2 subunit. Co-crystal structures of THN27 with CK2alpha and CK2alpha' reveal that subtle differences in the conformational variability of the interdomain hinge region are correlated with the observed effect. In the case of CK2alpha', 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 CK2alpha'.
Diacritic Binding of an Indenoindole Inhibitor by CK2alpha Paralogs Explored by a Reliable Path to Atomic Resolution CK2alpha' Structures.,Lindenblatt D, Nickelsen A, Applegate VM, Hochscherf J, Witulski B, Bouaziz Z, Marminon C, Bretner M, Le Borgne M, Jose J, Niefind K ACS Omega. 2019 Mar 19;4(3):5471-5478. doi: 10.1021/acsomega.8b03415. eCollection, 2019 Mar 31. PMID:31559376[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H. A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell. 2001 Feb;7(2):283-92. PMID:11239457
- ↑ Sayed M, Pelech S, Wong C, Marotta A, Salh B. Protein kinase CK2 is involved in G2 arrest and apoptosis following spindle damage in epithelial cells. Oncogene. 2001 Oct 25;20(48):6994-7005. PMID:11704824 doi:10.1038/sj.onc.1204894
- ↑ Shin S, Lee Y, Kim W, Ko H, Choi H, Kim K. Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J. 2005 Oct 19;24(20):3532-42. Epub 2005 Sep 29. PMID:16193064 doi:10.1038/sj.emboj.7600827
- ↑ Lindenblatt D, Nickelsen A, Applegate VM, Hochscherf J, Witulski B, Bouaziz Z, Marminon C, Bretner M, Le Borgne M, Jose J, Niefind K. Diacritic Binding of an Indenoindole Inhibitor by CK2alpha Paralogs Explored by a Reliable Path to Atomic Resolution CK2alpha' Structures. ACS Omega. 2019 Mar 19;4(3):5471-5478. doi: 10.1021/acsomega.8b03415. eCollection, 2019 Mar 31. PMID:31559376 doi:http://dx.doi.org/10.1021/acsomega.8b03415
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