6qxu

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Current revision (07:37, 1 May 2024) (edit) (undo)
 
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<StructureSection load='6qxu' size='340' side='right'caption='[[6qxu]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
<StructureSection load='6qxu' size='340' side='right'caption='[[6qxu]], [[Resolution|resolution]] 1.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6qxu]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QXU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QXU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6qxu]] 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=6QXU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QXU 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=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=JKN:6,8-bis(fluoranyl)-2-[4-(2-oxidanylpropan-2-yl)phenyl]-3~{H}-quinazolin-4-one'>JKN</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]] 1.2&#8491;</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=6qxu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qxu OCA], [http://pdbe.org/6qxu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qxu RCSB], [http://www.ebi.ac.uk/pdbsum/6qxu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qxu ProSAT]</span></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=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=JKN:6,8-bis(fluoranyl)-2-[4-(2-oxidanylpropan-2-yl)phenyl]-3~{H}-quinazolin-4-one'>JKN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6qxu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qxu OCA], [https://pdbe.org/6qxu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qxu RCSB], [https://www.ebi.ac.uk/pdbsum/6qxu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qxu ProSAT]</span></td></tr>
</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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Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological targets which recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the phenyl residue. These efforts were supported by analysis of TNKS X-ray and Watermap structures and resulted in compound 5k, a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of 5k in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compound in a colorectal xenograft model in vivo.
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Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity.,Buchstaller HP, Anlauf U, Dorsch D, Kuhn D, Lehmann M, Leuthner B, Musil D, Radtki D, Ritzert C, Rohdich F, Schneider R, Esdar C J Med Chem. 2019 Aug 5. doi: 10.1021/acs.jmedchem.9b00656. PMID:31381853<ref>PMID:31381853</ref>
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==See Also==
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*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
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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 6qxu" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Buchstaller, H P]]
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[[Category: Buchstaller H-P]]
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[[Category: Lehmann, D]]
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[[Category: Lehmann D]]
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[[Category: Musil, D]]
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[[Category: Musil D]]
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[[Category: Inhibitor]]
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[[Category: Parp]]
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[[Category: Tankyrase]]
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[[Category: Transferase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Human TNKS1 in complex with 6,8-Difluoro-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3H-quinazolin-4-one

PDB ID 6qxu

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