4jsr - Revision history

OCA at 12:06, 1 March 2024

OCA — Fri, 01 Mar 2024 12:06:31 GMT

←Older revision		Revision as of 12:06, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4jsr]] 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=4JSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JSR FirstGlance]. <br>		<table><tr><td colspan='2'>[[4jsr]] 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=4JSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JSR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1NQ:N-{2-[1-(6-CARBAMOYLTHIENO[3,2-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]ETHYL}-N-ETHYLTHIOPHENE-2,5-DICARBOXAMIDE'>1NQ</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]] 1.7Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1NQ:N-{2-[1-(6-CARBAMOYLTHIENO[3,2-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]ETHYL}-N-ETHYLTHIOPHENE-2,5-DICARBOXAMIDE'>1NQ</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=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [https://pdbe.org/4jsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [https://www.ebi.ac.uk/pdbsum/4jsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jsr 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=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [https://pdbe.org/4jsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [https://www.ebi.ac.uk/pdbsum/4jsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jsr ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>		[https://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	The sirtuins SIRT1, SIRT2 and SIRT3 are NAD+ dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic and neurodegenerative disorders. Encoded Library Technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g. 11c: IC50 = 3.6, 2.7 and 4.0 nM for SIRT1, SIRT2 and SIRT3 respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogs 28 and 31. Crystallographic studies of 11c, 28 and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors which makes them valuable tools for sirtuin research.
-
-	Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3.,Disch JS, Evindar G, Chui CH, Blum CA, Dai H, Jin L, Schuman E, Lind KE, Belyanskaya SL, Deng J, Coppo FT, Aquilani L, Graybill TL, Cuozzo JW, Lavu S, Mao C, Vlasuk GP, Perni RB J Med Chem. 2013 Apr 9. PMID:23570514<ref>PMID:23570514</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4jsr" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 11:23, 30 November 2022

OCA — Wed, 30 Nov 2022 11:23:47 GMT

←Older revision		Revision as of 11:23, 30 November 2022
Line 1:		Line 1:

	==Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]==		==Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]==
-	<StructureSection load='4jsr' size='340' side='right' caption='[[4jsr]], [[Resolution\|resolution]] 1.70Å' scene=''>	+	<StructureSection load='4jsr' size='340' side='right'caption='[[4jsr]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4jsr]] 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=4JSR OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4JSR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4jsr]] 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=4JSR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JSR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1NQ:N-{2-[1-(6-CARBAMOYLTHIENO[3,2-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]ETHYL}-N-ETHYLTHIOPHENE-2,5-DICARBOXAMIDE'>1NQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1NQ:N-{2-[1-(6-CARBAMOYLTHIENO[3,2-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]ETHYL}-N-ETHYLTHIOPHENE-2,5-DICARBOXAMIDE'>1NQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jt8\|4jt8]], [[4jt9\|4jt9]]</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=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [https://pdbe.org/4jsr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [https://www.ebi.ac.uk/pdbsum/4jsr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jsr ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">SIRT3, SIR2L3 ([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~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [~~http~~://pdbe.org/4jsr PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4jsr PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4jsr ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN]] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>	+	[https://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 20:

	==See Also==		==See Also==
-	*[[Histone deacetylase\|Histone deacetylase]]	+	*[[Histone deacetylase 3D structures\|Histone deacetylase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Dai, H~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Deacetylase]]~~	+	[[Category: Dai H]]
-	~~[[Category: Hydrolase-hydrolase inhibitor complex~~]]	+

OCA at 19:27, 4 August 2016

OCA — Thu, 04 Aug 2016 19:27:02 GMT

←Older revision		Revision as of 19:27, 4 August 2016
Line 1:		Line 1:
		+
	==Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]==		==Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]==
	<StructureSection load='4jsr' size='340' side='right' caption='[[4jsr]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='4jsr' size='340' side='right' caption='[[4jsr]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4jsr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JSR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JSR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4jsr]] 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=4JSR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JSR FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1NQ:N-{2-[1-(6-CARBAMOYLTHIENO[3,2-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]ETHYL}-N-ETHYLTHIOPHENE-2,5-DICARBOXAMIDE'>1NQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1NQ:N-{2-[1-(6-CARBAMOYLTHIENO[3,2-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]ETHYL}-N-ETHYLTHIOPHENE-2,5-DICARBOXAMIDE'>1NQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jt8\|4jt8]], [[4jt9\|4jt9]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jt8\|4jt8]], [[4jt9\|4jt9]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">SIRT3, SIR2L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">SIRT3, SIR2L3 ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [http://www.ebi.ac.uk/pdbsum/4jsr PDBsum]</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=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [http://pdbe.org/4jsr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [http://www.ebi.ac.uk/pdbsum/4jsr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jsr ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4jsr" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Histone deacetylase\|Histone deacetylase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Dai, H]]		[[Category: Dai, H]]
	[[Category: Deacetylase]]		[[Category: Deacetylase]]
	[[Category: Hydrolase-hydrolase inhibitor complex]]		[[Category: Hydrolase-hydrolase inhibitor complex]]

OCA at 12:23, 25 December 2014

OCA — Thu, 25 Dec 2014 12:23:54 GMT

←Older revision		Revision as of 12:23, 25 December 2014
Line 8:		Line 8:
	<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=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [http://www.ebi.ac.uk/pdbsum/4jsr PDBsum]</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=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [http://www.ebi.ac.uk/pdbsum/4jsr PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN]] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 14:44, 21 December 2014

OCA — Sun, 21 Dec 2014 14:44:55 GMT

←Older revision		Revision as of 14:44, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4jsr\| PDB=4jsr \| SCENE= }}~~	+	==Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]==
-	===Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]===	+	<StructureSection load='4jsr' size='340' side='right' caption='[[4jsr]], [[Resolution\|resolution]] 1.70Å' scene=''>
-	{~~{ABSTRACT_PUBMED_23570514}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4jsr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JSR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JSR FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1NQ:N-{2-[1-(6-CARBAMOYLTHIENO[3,2-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]ETHYL}-N-ETHYLTHIOPHENE-2,5-DICARBOXAMIDE'>1NQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jt8\|4jt8]], [[4jt9\|4jt9]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">SIRT3, SIR2L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4jsr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jsr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4jsr RCSB], [http://www.ebi.ac.uk/pdbsum/4jsr PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The sirtuins SIRT1, SIRT2 and SIRT3 are NAD+ dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic and neurodegenerative disorders. Encoded Library Technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g. 11c: IC50 = 3.6, 2.7 and 4.0 nM for SIRT1, SIRT2 and SIRT3 respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogs 28 and 31. Crystallographic studies of 11c, 28 and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors which makes them valuable tools for sirtuin research.

-	~~==Function==~~	+	Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3.,Disch JS, Evindar G, Chui CH, Blum CA, Dai H, Jin L, Schuman E, Lind KE, Belyanskaya SL, Deng J, Coppo FT, Aquilani L, Graybill TL, Cuozzo JW, Lavu S, Mao C, Vlasuk GP, Perni RB J Med Chem. 2013 Apr 9. PMID:23570514<ref>PMID:23570514</ref>
-	[~~[http://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN~~]~~] NAD~~-~~dependent protein deacetylase~~. ~~Activates mitochondrial target proteins~~, ~~including ACSS1~~, ~~IDH2 and GDH by deacetylating key lysine residues~~. ~~Contributes to the regulation of the cellular energy metabolism~~. ~~Important for regulating tissue-specific ATP levels.<ref>~~PMID:~~16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref>~~ <ref>PMID:~~19535340~~</ref>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4jsr]] is~~ a ~~1 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=4JSR OCA].~~	+	</div>
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:023570514</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Dai, H.]]	+	[[Category: Dai, H]]
	[[Category: Deacetylase]]		[[Category: Deacetylase]]
	[[Category: Hydrolase-hydrolase inhibitor complex]]		[[Category: Hydrolase-hydrolase inhibitor complex]]

OCA at 12:33, 3 July 2013

OCA — Wed, 03 Jul 2013 12:33:20 GMT

←Older revision		Revision as of 12:33, 3 July 2013
Line 10:		Line 10:

	==Reference==		==Reference==
-	<references group="xtra"/><references/>	+	<ref group="xtra">PMID:023570514</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Dai, H.]]		[[Category: Dai, H.]]
	[[Category: Deacetylase]]		[[Category: Deacetylase]]
	[[Category: Hydrolase-hydrolase inhibitor complex]]		[[Category: Hydrolase-hydrolase inhibitor complex]]

OCA at 11:22, 24 April 2013

OCA — Wed, 24 Apr 2013 11:22:00 GMT

←Older revision		Revision as of 11:22, 24 April 2013
Line 1:		Line 1:
-	'~~''Unreleased structure'''~~	+	{{STRUCTURE_4jsr\| PDB=4jsr \| SCENE= }}
		+	===Crystal Structure of human SIRT3 with ELT inhibitor 11c [N-{2-[1-(6-carbamoylthieno[3,2-d]pyrimidin-4-yl)piperidin-4-yl]ethyl}-N'-ethylthiophene-2,5-dicarboxamide]===
		+	{{ABSTRACT_PUBMED_23570514}}

-	~~The entry 4jsr is ON HOLD~~	+	==Function==
		+	[[http://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN]] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>

-	~~Authors~~: ~~Dai, H~~.	+	==About this Structure==
		+	[[4jsr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JSR OCA].

-	~~Description~~:	+	==Reference==
		+	<references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Dai, H.]]
		+	[[Category: Deacetylase]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]

OCA at 19:59, 17 April 2013

OCA — Wed, 17 Apr 2013 19:59:13 GMT

←Older revision		Revision as of 19:59, 17 April 2013
Line 5:		Line 5:
	Authors: Dai, H.		Authors: Dai, H.

-	Description: ~~Crystal Structure of human SIRT3 with ELT inhibitor 11c~~	+	Description:

OCA: Protected "4jsr" [edit=sysop:move=sysop]

OCA — Thu, 04 Apr 2013 01:00:23 GMT

Protected "4jsr" [edit=sysop:move=sysop]

←Older revision

Revision as of 01:00, 4 April 2013

OCA: New page: '''Unreleased structure''' The entry 4jsr is ON HOLD Authors: Dai, H. Description: Crystal Structure of human SIRT3 with ELT inhibitor 11c

OCA — Thu, 04 Apr 2013 01:00:22 GMT

New page: '''Unreleased structure''' The entry 4jsr is ON HOLD Authors: Dai, H. Description: Crystal Structure of human SIRT3 with ELT inhibitor 11c

New page

'''Unreleased structure'''

The entry 4jsr is ON HOLD

Authors: Dai, H.

Description: Crystal Structure of human SIRT3 with ELT inhibitor 11c