6tkr

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==Tankyrase 2 in complex with an inhibitor (OM-1704)==
==Tankyrase 2 in complex with an inhibitor (OM-1704)==
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<StructureSection load='6tkr' size='340' side='right'caption='[[6tkr]]' scene=''>
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<StructureSection load='6tkr' size='340' side='right'caption='[[6tkr]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TKR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TKR FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6tkr]] 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=6TKR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TKR FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6tkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tkr OCA], [http://pdbe.org/6tkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tkr RCSB], [http://www.ebi.ac.uk/pdbsum/6tkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tkr ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NJK:~{N}-[3-[5-(5-ethoxypyridin-2-yl)-4-(2-fluorophenyl)-1,2,4-triazol-3-yl]cyclobutyl]-1,5-naphthyridine-2-carboxamide'>NJK</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'>[http://proteopedia.org/fgij/fg.htm?mol=6tkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tkr OCA], [http://pdbe.org/6tkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tkr RCSB], [http://www.ebi.ac.uk/pdbsum/6tkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tkr ProSAT]</span></td></tr>
</table>
</table>
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== 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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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>
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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 6tkr" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Lehtio L]]
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[[Category: Lehtio, L]]
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[[Category: Sowa ST]]
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[[Category: Sowa, S T]]
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[[Category: Complex]]
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[[Category: Enzyme]]
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[[Category: Inhibitor]]
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[[Category: Poly-adp-ribosylation]]
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[[Category: Transferase]]

Revision as of 11:34, 22 July 2020

Tankyrase 2 in complex with an inhibitor (OM-1704)

PDB ID 6tkr

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