4buf: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4buf]] 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=4BUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BUF FirstGlance]. <br> | <table><tr><td colspan='2'>[[4buf]] 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=4BUF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BUF FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F36:2-(4-ACETYLPHENYL)-3,4-DIHYDROQUINAZOLIN-4-ONE'>F36</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F36:2-(4-ACETYLPHENYL)-3,4-DIHYDROQUINAZOLIN-4-ONE'>F36</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4buf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4buf OCA], [https://pdbe.org/4buf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4buf RCSB], [https://www.ebi.ac.uk/pdbsum/4buf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4buf ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4buf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4buf OCA], [https://pdbe.org/4buf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4buf RCSB], [https://www.ebi.ac.uk/pdbsum/4buf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4buf ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold's phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain. | |||
para-Substituted 2-Phenyl-3,4-dihydroquinazolin-4-ones As Potent and Selective Tankyrase Inhibitors.,Haikarainen T, Koivunen J, Narwal M, Venkannagari H, Obaji E, Joensuu P, Pihlajaniemi T, Lehtio L ChemMedChem. 2013 Oct 15. doi: 10.1002/cmdc.201300337. PMID:24130191<ref>PMID:24130191</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4buf" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
Latest revision as of 14:05, 9 May 2024
Crystal structure of human tankyrase 2 in complex with 2-(4- acetylphenyl)-3,4-dihydroquinazolin-4-oneCrystal structure of human tankyrase 2 in complex with 2-(4- acetylphenyl)-3,4-dihydroquinazolin-4-one
Structural highlights
FunctionTNKS2_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.[1] [2] [3] [4] Publication Abstract from PubMedHuman tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold's phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain. para-Substituted 2-Phenyl-3,4-dihydroquinazolin-4-ones As Potent and Selective Tankyrase Inhibitors.,Haikarainen T, Koivunen J, Narwal M, Venkannagari H, Obaji E, Joensuu P, Pihlajaniemi T, Lehtio L ChemMedChem. 2013 Oct 15. doi: 10.1002/cmdc.201300337. PMID:24130191[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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