4n4v

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==Co-crystal structure of tankyrase 1 with compound 4 [(4S)-3-{trans-4-[6-amino-5-(pyrimidin-2-yl)pyridin-3-yl]cyclohexyl}-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one]==
==Co-crystal structure of tankyrase 1 with compound 4 [(4S)-3-{trans-4-[6-amino-5-(pyrimidin-2-yl)pyridin-3-yl]cyclohexyl}-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one]==
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<StructureSection load='4n4v' size='340' side='right' caption='[[4n4v]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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<StructureSection load='4n4v' size='340' side='right'caption='[[4n4v]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4n4v]] 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=4N4V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N4V FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4n4v]] 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=4N4V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N4V 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=2GY:(4S)-3-{TRANS-4-[6-AMINO-5-(PYRIMIDIN-2-YL)PYRIDIN-3-YL]CYCLOHEXYL}-5,5-DIMETHYL-4-PHENYL-1,3-OXAZOLIDIN-2-ONE'>2GY</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&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4k4f|4k4f]], [[4n3r|4n3r]], [[4n4t|4n4t]]</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=2GY:(4S)-3-{TRANS-4-[6-AMINO-5-(PYRIMIDIN-2-YL)PYRIDIN-3-YL]CYCLOHEXYL}-5,5-DIMETHYL-4-PHENYL-1,3-OXAZOLIDIN-2-ONE'>2GY</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=4n4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n4v OCA], [https://pdbe.org/4n4v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n4v RCSB], [https://www.ebi.ac.uk/pdbsum/4n4v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n4v 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=4n4v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n4v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4n4v RCSB], [http://www.ebi.ac.uk/pdbsum/4n4v PDBsum]</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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Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.
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Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.,Huang H, Guzman-Perez A, Acquaviva L, Berry V, Bregman H, Dovey J, Gunaydin H, Huang X, Huang L, Saffran D, Serafino R, Schneider S, Wilson C, DiMauro EF ACS Med Chem Lett. 2013 Oct 21;4(12):1218-23. doi: 10.1021/ml4003315. eCollection, 2013 Dec 12. PMID:24900633<ref>PMID:24900633</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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==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: Huang, X]]
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[[Category: Large Structures]]
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[[Category: Inhibitor]]
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[[Category: Huang X]]
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[[Category: Parp]]
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[[Category: Tankyrase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Co-crystal structure of tankyrase 1 with compound 4 [(4S)-3-{trans-4-[6-amino-5-(pyrimidin-2-yl)pyridin-3-yl]cyclohexyl}-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one]

PDB ID 4n4v

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