6r8r - Revision history

OCA at 12:17, 24 January 2024

OCA — Wed, 24 Jan 2024 12:17:19 GMT

←Older revision		Revision as of 12:17, 24 January 2024
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	<StructureSection load='6r8r' size='340' side='right'caption='[[6r8r]], [[Resolution\|resolution]] 1.27Å' scene=''>		<StructureSection load='6r8r' size='340' side='right'caption='[[6r8r]], [[Resolution\|resolution]] 1.27Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6r8r]] is a 1 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=6R8R OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6R8R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6r8r]] is a 1 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=6R8R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R8R FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JV8:~{N}-isoquinolin-6-yl-2-(2-methylphenoxy)ethanamide'>JV8</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.27Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NOTUM, OK/SW-CL.30 ([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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JV8:~{N}-isoquinolin-6-yl-2-(2-methylphenoxy)ethanamide'>JV8</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.98 3.1.1.98] </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=6r8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8r OCA], [https://pdbe.org/6r8r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r8r RCSB], [https://www.ebi.ac.uk/pdbsum/6r8r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8r ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6r8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8r OCA], [~~http~~://pdbe.org/6r8r PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6r8r RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6r8r PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8r ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN]] May deacetylate GlcNAc residues on cell surface glycans.	+	[https://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN] May deacetylate GlcNAc residues on cell surface glycans.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC(50) 33 muM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC(50) 0.032 muM) and isoquinoline 45 (IC(50) 0.085 muM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to 3. However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.
		+
		+	Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen.,Atkinson BN, Steadman D, Zhao Y, Sipthorp J, Vecchia L, Ruza RR, Jeganathan F, Lines G, Frew S, Monaghan A, Kjaer S, Bictash M, Jones EY, Fish PV Medchemcomm. 2019 Apr 29;10(8):1361-1369. doi: 10.1039/c9md00096h. eCollection , 2019 Aug 1. PMID:31534655<ref>PMID:31534655</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6r8r" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Carboxylesterase 3D structures\|Carboxylesterase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Jones~~, E Y~~]]	+	[[Category: Jones EY]]
-	[[Category: Ruza~~, R R~~]]	+	[[Category: Ruza RR]]
-	[[Category: Vecchia, L]]	+	[[Category: Vecchia L]]
-	[[Category: Zhao, Y]]	+	[[Category: Zhao Y]]
-	~~[[Category: Crystallographic fragment screen]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Notum inhibitor]]~~	+
-	~~[[Category: Wnt signalling~~]]	+

OCA at 06:41, 10 July 2019

OCA — Wed, 10 Jul 2019 06:41:44 GMT

←Older revision		Revision as of 06:41, 10 July 2019
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	<StructureSection load='6r8r' size='340' side='right'caption='[[6r8r]], [[Resolution\|resolution]] 1.27Å' scene=''>		<StructureSection load='6r8r' size='340' side='right'caption='[[6r8r]], [[Resolution\|resolution]] 1.27Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6r8r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R8R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6r8r]] is a 1 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=6R8R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R8R FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JV8:~{N}-isoquinolin-6-yl-2-(2-methylphenoxy)ethanamide'>JV8</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JV8:~{N}-isoquinolin-6-yl-2-(2-methylphenoxy)ethanamide'>JV8</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NOTUM, OK/SW-CL.30 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.98 3.1.1.98] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.98 3.1.1.98] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6r8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8r OCA], [http://pdbe.org/6r8r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r8r RCSB], [http://www.ebi.ac.uk/pdbsum/6r8r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8r ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6r8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8r OCA], [http://pdbe.org/6r8r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r8r RCSB], [http://www.ebi.ac.uk/pdbsum/6r8r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8r ProSAT]</span></td></tr>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Jones, E Y]]		[[Category: Jones, E Y]]

OCA at 11:28, 10 May 2019

OCA — Fri, 10 May 2019 11:28:42 GMT

←Older revision		Revision as of 11:28, 10 May 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6r8r ~~is ON HOLD until Paper Publication~~	+	==Structure of the Wnt deacylase Notum in complex with isoquinoline 45==
-		+	<StructureSection load='6r8r' size='340' side='right'caption='[[6r8r]], [[Resolution\|resolution]] 1.27Å' scene=''>
-	~~Authors~~: ~~Vecchia~~, L., ~~Zhao~~, Y., ~~Ruza~~, R.R., ~~Jones, E~~.Y.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6r8r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R8R FirstGlance]. <br>
-	~~Description~~: ~~Structure of the Wnt deacylase Notum in complex with isoquinoline 45~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JV8:~{N}-isoquinolin-6-yl-2-(2-methylphenoxy)ethanamide'>JV8</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Wnt_protein]_O-palmitoleoyl-L-serine_hydrolase [Wnt protein] O-palmitoleoyl-L-serine hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.1.98 3.1.1.98] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6r8r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8r OCA], [http://pdbe.org/6r8r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r8r RCSB], [http://www.ebi.ac.uk/pdbsum/6r8r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8r ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/NOTUM_HUMAN NOTUM_HUMAN]] May deacetylate GlcNAc residues on cell surface glycans.
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Jones, E Y]]
		+	[[Category: Ruza, R R]]
	[[Category: Vecchia, L]]		[[Category: Vecchia, L]]
	[[Category: Zhao, Y]]		[[Category: Zhao, Y]]
-	[[Category: ~~Jones, E.Y~~]]	+	[[Category: Crystallographic fragment screen]]
-	[[Category: ~~Ruza, R.R~~]]	+	[[Category: Hydrolase]]
		+	[[Category: Notum inhibitor]]
		+	[[Category: Wnt signalling]]

OCA: Protected "6r8r" [edit=sysop:move=sysop]

OCA — Wed, 10 Apr 2019 05:44:22 GMT

Protected "6r8r" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:44, 10 April 2019

OCA: New page: '''Unreleased structure''' The entry 6r8r is ON HOLD until Paper Publication Authors: Vecchia, L., Zhao, Y., Ruza, R.R., Jones, E.Y. Description: Structure of the Wnt deacylase Notum i...

OCA — Wed, 10 Apr 2019 05:44:21 GMT

New page: '''Unreleased structure''' The entry 6r8r is ON HOLD until Paper Publication Authors: Vecchia, L., Zhao, Y., Ruza, R.R., Jones, E.Y. Description: Structure of the Wnt deacylase Notum i...

New page

'''Unreleased structure'''

The entry 6r8r is ON HOLD until Paper Publication

Authors: Vecchia, L., Zhao, Y., Ruza, R.R., Jones, E.Y.

Description: Structure of the Wnt deacylase Notum in complex with isoquinoline 45
[[Category: Unreleased Structures]]
[[Category: Vecchia, L]]
[[Category: Zhao, Y]]
[[Category: Jones, E.Y]]
[[Category: Ruza, R.R]]