4bu9: Difference between revisions
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==Crystal structure of human tankyrase 2 in complex with 2-(4- methoxyphenyl)-3,4-dihydroquinazolin-4-one== | ==Crystal structure of human tankyrase 2 in complex with 2-(4- methoxyphenyl)-3,4-dihydroquinazolin-4-one== | ||
<StructureSection load='4bu9' size='340' side='right' caption='[[4bu9]], [[Resolution|resolution]] 1.65Å' scene=''> | <StructureSection load='4bu9' size='340' side='right'caption='[[4bu9]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4bu9]] 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=4BU9 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[4bu9]] 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=4BU9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=4BU9 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=08C:2-(4-METHOXYPHENYL)-3,4-DIHYDROQUINAZOLIN-4-ONE'>08C</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=08C:2-(4-METHOXYPHENYL)-3,4-DIHYDROQUINAZOLIN-4-ONE'>08C</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bu3|4bu3]], [[4bu5|4bu5]], [[4bu6|4bu6]], [[4bu7|4bu7]], [[4bu8|4bu8]], [[4bua|4bua]], [[4bud|4bud]], [[4bue|4bue]], [[4buf|4buf]], [[4bui|4bui]], [[4bus|4bus]], [[4but|4but]], [[4buu|4buu]], [[4buv|4buv]], [[4buw|4buw]], [[4bux|4bux]], [[4buy|4buy]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bu3|4bu3]], [[4bu5|4bu5]], [[4bu6|4bu6]], [[4bu7|4bu7]], [[4bu8|4bu8]], [[4bua|4bua]], [[4bud|4bud]], [[4bue|4bue]], [[4buf|4buf]], [[4bui|4bui]], [[4bus|4bus]], [[4but|4but]], [[4buu|4buu]], [[4buv|4buv]], [[4buw|4buw]], [[4bux|4bux]], [[4buy|4buy]]</td></tr> | ||
<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> | <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> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=4bu9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bu9 OCA], [http://pdbe.org/4bu9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bu9 RCSB], [http://www.ebi.ac.uk/pdbsum/4bu9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bu9 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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==See Also== | ==See Also== | ||
*[[Poly (ADP-ribose) polymerase|Poly (ADP-ribose) polymerase]] | *[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Haikarainen, T]] | [[Category: Haikarainen, T]] | ||
[[Category: Lehtio, L]] | [[Category: Lehtio, L]] | ||
Revision as of 11:15, 4 November 2020
Crystal structure of human tankyrase 2 in complex with 2-(4- methoxyphenyl)-3,4-dihydroquinazolin-4-oneCrystal structure of human tankyrase 2 in complex with 2-(4- methoxyphenyl)-3,4-dihydroquinazolin-4-one
Structural highlights
Function[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.[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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