6tkp: Difference between revisions
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==Tankyrase 2 in complex with an inhibitor (OM-1900)== | ==Tankyrase 2 in complex with an inhibitor (OM-1900)== | ||
<StructureSection load='6tkp' size='340' side='right'caption='[[6tkp]]' scene=''> | <StructureSection load='6tkp' size='340' side='right'caption='[[6tkp]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TKP OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6tkp]] 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=6TKP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TKP FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NJB:~{N}-[3-[4-(2-chlorophenyl)-5-(5-ethoxypyridin-2-yl)-1,2,4-triazol-3-yl]cyclobutyl]-1,5-naphthyridine-4-carboxamide'>NJB</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=6tkp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tkp OCA], [https://pdbe.org/6tkp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tkp RCSB], [https://www.ebi.ac.uk/pdbsum/6tkp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tkp ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== 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 == | |||
Tankyrases 1 and 2 are central biotargets in the WNT/beta-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/beta-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro. | |||
Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.,Waaler J, Leenders RGG, Sowa ST, Alam Brinch S, Lycke M, Nieczypor P, Aertssen S, Murthy S, Galera-Prat A, Damen E, Wegert A, Nazare M, Lehtio L, Krauss S J Med Chem. 2020 Jun 23. doi: 10.1021/acs.jmedchem.0c00208. PMID:32511917<ref>PMID:32511917</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tkp" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lehtio L]] | [[Category: Lehtio L]] | ||
[[Category: Sowa ST]] | [[Category: Sowa ST]] | ||