5mat: Difference between revisions
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==Structure of human Sirtuin 2 in complex with a selective thienopyrimidinone based inhibitor== | ==Structure of human Sirtuin 2 in complex with a selective thienopyrimidinone based inhibitor== | ||
<StructureSection load='5mat' size='340' side='right' caption='[[5mat]], [[Resolution|resolution]] 2.07Å' scene=''> | <StructureSection load='5mat' size='340' side='right'caption='[[5mat]], [[Resolution|resolution]] 2.07Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5mat]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MAT OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5mat]] 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=5MAT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MAT FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7KJ:(7~{R})-7-[(3,5-DIMETHYL-1,2-OXAZOL-4-YL)METHYLAMINO]-3-[(4-METHOXYNAPHTHALEN-1-YL)METHYL]-5,6,7,8-TETRAHYDRO-[1]BENZOTHIOLO[2,3-D]PYRIMIDIN-4-ONE'>7KJ</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7KJ:(7~{R})-7-[(3,5-DIMETHYL-1,2-OXAZOL-4-YL)METHYLAMINO]-3-[(4-METHOXYNAPHTHALEN-1-YL)METHYL]-5,6,7,8-TETRAHYDRO-[1]BENZOTHIOLO[2,3-D]PYRIMIDIN-4-ONE'>7KJ</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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:// | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SIRT2, SIR2L, SIR2L2 ([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=5mat FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mat OCA], [http://pdbe.org/5mat PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mat RCSB], [http://www.ebi.ac.uk/pdbsum/5mat PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mat ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5mat" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5mat" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Moniot, S]] | [[Category: Moniot, S]] | ||
[[Category: Steegborn, C]] | [[Category: Steegborn, C]] | ||
Revision as of 10:14, 19 August 2020
Structure of human Sirtuin 2 in complex with a selective thienopyrimidinone based inhibitorStructure of human Sirtuin 2 in complex with a selective thienopyrimidinone based inhibitor
Structural highlights
Function[SIR2_HUMAN] NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.[1] [2] [3] [4] Publication Abstract from PubMedSirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors. Thienopyrimidinone Based Sirtuin-2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket.,Sundriyal S, Moniot S, Mahmud Z, Yao S, Di Fruscia P, Reynolds CR, Dexter DT, Sternberg MJ, Lam EW, Steegborn C, Fuchter MJ J Med Chem. 2017 Feb 15. doi: 10.1021/acs.jmedchem.6b01690. PMID:28135086[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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