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3ua9

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==Crystal structure of human tankyrase 2 in complex with a selective inhibitor==
==Crystal structure of human tankyrase 2 in complex with a selective inhibitor==
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<StructureSection load='3ua9' size='340' side='right' caption='[[3ua9]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
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<StructureSection load='3ua9' size='340' side='right'caption='[[3ua9]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3ua9]] 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=3UA9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UA9 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3ua9]] 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=3UA9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UA9 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=IWR:4-[(3AR,4S,7R,7AS)-1,3-DIOXO-1,3,3A,4,7,7A-HEXAHYDRO-2H-4,7-METHANOISOINDOL-2-YL]-N-(QUINOLIN-8-YL)BENZAMIDE'>IWR</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.15&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3u9h|3u9h]], [[3u9y|3u9y]]</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=IWR:4-[(3AR,4S,7R,7AS)-1,3-DIOXO-1,3,3A,4,7,7A-HEXAHYDRO-2H-4,7-METHANOISOINDOL-2-YL]-N-(QUINOLIN-8-YL)BENZAMIDE'>IWR</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">TNKS2, PARP5B, TANK2, TNKL ([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=3ua9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ua9 OCA], [https://pdbe.org/3ua9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ua9 RCSB], [https://www.ebi.ac.uk/pdbsum/3ua9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ua9 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=3ua9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ua9 OCA], [http://pdbe.org/3ua9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ua9 RCSB], [http://www.ebi.ac.uk/pdbsum/3ua9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ua9 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/TNKS2_HUMAN TNKS2_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 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 poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles.<ref>PMID:11802774</ref> <ref>PMID:11739745</ref> <ref>PMID:19759537</ref> <ref>PMID:21478859</ref>
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[https://www.uniprot.org/uniprot/TNKS2_HUMAN TNKS2_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 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 poly-ADP-ribosylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates poly-ADP-ribosylation of TERF1, thereby contributing to the regulation of telomere length. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles.<ref>PMID:11802774</ref> <ref>PMID:11739745</ref> <ref>PMID:19759537</ref> <ref>PMID:21478859</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a by-product, nicotinamide and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induce specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, which does not bind to the widely-utilized nicotinamide-binding site makes the structure valuable also for development of PARP inhibitors in general.
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Structural Basis of Selective Inhibition of Human Tankyrases.,Narwal M, Venkannagari H, Lehtio L J Med Chem. 2012 Jan 10. PMID:22233320<ref>PMID:22233320</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 3ua9" 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: Lehtio, L]]
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[[Category: Large Structures]]
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[[Category: Narwal, M]]
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[[Category: Lehtio L]]
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[[Category: Adp-ribosylation]]
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[[Category: Narwal M]]
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[[Category: Diphtheria toxin like fold]]
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[[Category: Protein-ligand complex]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structure of human tankyrase 2 in complex with a selective inhibitor

PDB ID 3ua9

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