6kro: Difference between revisions

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<StructureSection load='6kro' size='340' side='right'caption='[[6kro]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
<StructureSection load='6kro' size='340' side='right'caption='[[6kro]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6kro]] 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=6KRO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6KRO FirstGlance]. <br>
<table><tr><td colspan='2'>[[6kro]] 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=6KRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KRO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DU9:6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-4-fluoranyl-1-methyl-1-(8-methyl-4-oxidanylidene-3,5,6,7-tetrahydropyrido[2,3-d]pyrimidin-2-yl)spiro[indole-3,4-piperidine]-2-one'>DU9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.9&#8491;</td></tr>
<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>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DU9:6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-4-fluoranyl-1-methyl-1-(8-methyl-4-oxidanylidene-3,5,6,7-tetrahydropyrido[2,3-d]pyrimidin-2-yl)spiro[indole-3,4-piperidine]-2-one'>DU9</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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'>[http://proteopedia.org/fgij/fg.htm?mol=6kro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kro OCA], [http://pdbe.org/6kro PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kro RCSB], [http://www.ebi.ac.uk/pdbsum/6kro PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kro 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=6kro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kro OCA], [https://pdbe.org/6kro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kro RCSB], [https://www.ebi.ac.uk/pdbsum/6kro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kro ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[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>
[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 (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/beta-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and beta-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.


Design and Discovery of an Orally Efficacious Spiroindolinone-based Tankyrase Inhibitor for the Treatment of Colon Cancer.,Shirai F, Mizutani A, Yashiroda Y, Tsumura T, Kano Y, Muramatsu Y, Chikada T, Yuki H, Niwa H, Sato S, Washizuka K, Koda Y, Mazaki Y, Jang MK, Yoshida H, Nagamori A, Okue M, Watanabe T, Kitamura K, Shitara E, Honma T, Umehara T, Shirouzu M, Fukami T, Seimiya H, Yoshida M, Koyama H J Med Chem. 2020 Mar 23. doi: 10.1021/acs.jmedchem.0c00045. PMID:32202790<ref>PMID:32202790</ref>
==See Also==
 
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6kro" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Niwa, H]]
[[Category: Niwa H]]
[[Category: Okue, M]]
[[Category: Okue M]]
[[Category: Sato, S]]
[[Category: Sato S]]
[[Category: Seimiya, H]]
[[Category: Seimiya H]]
[[Category: Shirai, F]]
[[Category: Shirai F]]
[[Category: Shirouzu, M]]
[[Category: Shirouzu M]]
[[Category: Tsumura, T]]
[[Category: Tsumura T]]
[[Category: Umehara, T]]
[[Category: Umehara T]]
[[Category: Adp-ribosylation]]
[[Category: Parp]]
[[Category: Tankyrase]]
[[Category: Transferase-transferase inhibitor complex]]
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