6tkr - Revision history

OCA at 13:04, 24 January 2024

OCA — Wed, 24 Jan 2024 13:04:19 GMT

←Older revision		Revision as of 13:04, 24 January 2024
Line 3:		Line 3:
	<StructureSection load='6tkr' size='340' side='right'caption='[[6tkr]], [[Resolution\|resolution]] 2.75Å' scene=''>		<StructureSection load='6tkr' size='340' side='right'caption='[[6tkr]], [[Resolution\|resolution]] 2.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<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>	+	<table><tr><td colspan='2'>[[6tkr]] 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=6TKR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TKR FirstGlance]. <br>
-	</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>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.75Å</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=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>
-	<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>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6tkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tkr OCA], [https://pdbe.org/6tkr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tkr RCSB], [https://www.ebi.ac.uk/pdbsum/6tkr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tkr 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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 6tkr" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6tkr" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Poly(ADP-ribose) polymerase 3D structures\|Poly(ADP-ribose) polymerase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Lehtio, L]]	+	[[Category: Lehtio L]]
-	[[Category: Sowa~~, S T]]~~	+	[[Category: Sowa ST]]
-	~~[[Category: Complex]]~~	+
-	~~[[Category: Enzyme]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Poly-adp-ribosylation]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 11:34, 22 July 2020

OCA — Wed, 22 Jul 2020 11:34:02 GMT

←Older revision		Revision as of 11:34, 22 July 2020
Line 1:		Line 1:

	==Tankyrase 2 in complex with an inhibitor (OM-1704)==		==Tankyrase 2 in complex with an inhibitor (OM-1704)==
-	<StructureSection load='6tkr' size='340' side='right'caption='[[6tkr]]' scene=''>	+	<StructureSection load='6tkr' size='340' side='right'caption='[[6tkr]], [[Resolution\|resolution]] 2.75Å' 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=6TKR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TKR FirstGlance]. <br>	+	<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>
-	</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>	+	</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>
		+	<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='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>
		+	== 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>
		+	<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 6tkr" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Lehtio L]]	+	[[Category: Lehtio, L]]
-	[[Category: Sowa ST]]	+	[[Category: Sowa, S T]]
		+	[[Category: Complex]]
		+	[[Category: Enzyme]]
		+	[[Category: Inhibitor]]
		+	[[Category: Poly-adp-ribosylation]]
		+	[[Category: Transferase]]

OCA at 14:06, 8 July 2020

OCA — Wed, 08 Jul 2020 14:06:29 GMT

←Older revision		Revision as of 14:06, 8 July 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 6tkr is ON HOLD until Paper Publication~~	+	==Tankyrase 2 in complex with an inhibitor (OM-1704)==
-		+	<StructureSection load='6tkr' size='340' side='right'caption='[[6tkr]]' scene=''>
-	~~Authors: Sowa, S.T., Lehtio, L.~~	+	== Structural highlights ==
-		+	<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>
-	~~Description:~~ Tankyrase 2 in complex with an inhibitor (OM-1704)	+	</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>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Sowa~~, S.T]]	+	__TOC__
-	[[Category: Lehtio, L]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Lehtio L]]
		+	[[Category: Sowa ST]]

OCA at 13:16, 29 January 2020

OCA — Wed, 29 Jan 2020 13:16:44 GMT

←Older revision		Revision as of 13:16, 29 January 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6tkr is ON HOLD	+	The entry 6tkr is ON HOLD until Paper Publication

	Authors: Sowa, S.T., Lehtio, L.		Authors: Sowa, S.T., Lehtio, L.
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	Description: Tankyrase 2 in complex with an inhibitor (OM-1704)		Description: Tankyrase 2 in complex with an inhibitor (OM-1704)
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Lehtio, L]]
	[[Category: Sowa, S.T]]		[[Category: Sowa, S.T]]
		+	[[Category: Lehtio, L]]

OCA: Protected "6tkr" [edit=sysop:move=sysop]

OCA — Wed, 04 Dec 2019 06:30:45 GMT

Protected "6tkr" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:30, 4 December 2019

OCA: New page: '''Unreleased structure''' The entry 6tkr is ON HOLD Authors: Sowa, S.T., Lehtio, L. Description: Tankyrase 2 in complex with an inhibitor (OM-1704) Category: Unreleased Structures...

OCA — Wed, 04 Dec 2019 06:30:43 GMT

New page: '''Unreleased structure''' The entry 6tkr is ON HOLD Authors: Sowa, S.T., Lehtio, L. Description: Tankyrase 2 in complex with an inhibitor (OM-1704) Category: Unreleased Structures...

New page

'''Unreleased structure'''

The entry 6tkr is ON HOLD

Authors: Sowa, S.T., Lehtio, L.

Description: Tankyrase 2 in complex with an inhibitor (OM-1704)
[[Category: Unreleased Structures]]
[[Category: Lehtio, L]]
[[Category: Sowa, S.T]]