4k4f

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==Co-crystal structure of TNKS1 with compound 18 [4-[(4S)-5,5-dimethyl-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-N-(quinolin-8-yl)benzamide]==
==Co-crystal structure of TNKS1 with compound 18 [4-[(4S)-5,5-dimethyl-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-N-(quinolin-8-yl)benzamide]==
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<StructureSection load='4k4f' size='340' side='right' caption='[[4k4f]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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<StructureSection load='4k4f' size='340' side='right'caption='[[4k4f]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4k4f]] is a 2 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=4K4F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K4F FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4k4f]] is a 2 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=4K4F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K4F 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=K4F:4-[(4S)-5,5-DIMETHYL-2-OXO-4-PHENYL-1,3-OXAZOLIDIN-3-YL]-N-(QUINOLIN-8-YL)BENZAMIDE'>K4F</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.9&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dvi|4dvi]], [[4k4e|4k4e]]</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=K4F:4-[(4S)-5,5-DIMETHYL-2-OXO-4-PHENYL-1,3-OXAZOLIDIN-3-YL]-N-(QUINOLIN-8-YL)BENZAMIDE'>K4F</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TNKS, PARP5A, PARPL, TIN1, TINF1, TNKS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4k4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k4f OCA], [https://pdbe.org/4k4f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k4f RCSB], [https://www.ebi.ac.uk/pdbsum/4k4f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k4f ProSAT]</span></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/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30] </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=4k4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k4f OCA], [http://pdbe.org/4k4f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4k4f RCSB], [http://www.ebi.ac.uk/pdbsum/4k4f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4k4f ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/TNKS1_HUMAN TNKS1_HUMAN]] Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.<ref>PMID:10988299</ref> <ref>PMID:11739745</ref> <ref>PMID:16076287</ref> <ref>PMID:19759537</ref> <ref>PMID:21478859</ref> <ref>PMID:22864114</ref>
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[https://www.uniprot.org/uniprot/TNKS1_HUMAN TNKS1_HUMAN] Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.<ref>PMID:10988299</ref> <ref>PMID:11739745</ref> <ref>PMID:16076287</ref> <ref>PMID:19759537</ref> <ref>PMID:21478859</ref> <ref>PMID:22864114</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates beta-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of beta-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
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Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors.,Bregman H, Chakka N, Guzman-Perez A, Gunaydin H, Gu Y, Huang X, Berry V, Liu J, Teffera Y, Huang L, Egge B, Mullady EL, Schneider S, Andrews PS, Mishra A, Newcomb J, Serafino R, Strathdee CA, Turci SM, Wilson C, Dimauro EF J Med Chem. 2013 May 23. PMID:23701517<ref>PMID:23701517</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4k4f" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Poly (ADP-ribose) polymerase|Poly (ADP-ribose) polymerase]]
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*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Bregman, H]]
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[[Category: Large Structures]]
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[[Category: DiMauro, E]]
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[[Category: Bregman H]]
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[[Category: Gunaydin, H]]
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[[Category: DiMauro E]]
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[[Category: Huang, X]]
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[[Category: Gunaydin H]]
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[[Category: Wilson, C]]
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[[Category: Huang X]]
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[[Category: Parp]]
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[[Category: Wilson C]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Co-crystal structure of TNKS1 with compound 18 [4-[(4S)-5,5-dimethyl-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-N-(quinolin-8-yl)benzamide]

PDB ID 4k4f

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