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4jsr

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==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]==
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<StructureSection load='4jsr' size='340' side='right' caption='[[4jsr]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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<StructureSection load='4jsr' size='340' side='right'caption='[[4jsr]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<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>
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<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>
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</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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jt8|4jt8]], [[4jt9|4jt9]]</td></tr>
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<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>
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<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>
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<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>
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<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>
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</table>
</table>
== Function ==
== Function ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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>
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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 4jsr" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Histone deacetylase|Histone deacetylase]]
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*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Dai, H]]
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[[Category: Large Structures]]
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[[Category: Deacetylase]]
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[[Category: Dai H]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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Current revision

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]

PDB ID 4jsr

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