View source for 5dy4


==Crystal structure of human Sirt2 in complex with a brominated 2nd generation SirReal inhibitor and NAD+==
<StructureSection load='5dy4' size='340' side='right'caption='[[5dy4]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5dy4]] 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=5DY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DY4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.77&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5GN:N-{5-[(7-BROMONAPHTHALEN-1-YL)METHYL]-1,3-THIAZOL-2-YL}-2-[(4,6-DIMETHYLPYRIMIDIN-2-YL)SULFANYL]ACETAMIDE'>5GN</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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=5dy4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dy4 OCA], [https://pdbe.org/5dy4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dy4 RCSB], [https://www.ebi.ac.uk/pdbsum/5dy4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dy4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SIR2_HUMAN 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.<ref>PMID:12620231</ref> <ref>PMID:12697818</ref> <ref>PMID:21081649</ref> <ref>PMID:21726808</ref> 
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== Publication Abstract from PubMed ==
Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl but also other acyl groups from the epsilon-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.

Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study.,Schiedel M, Rumpf T, Karaman B, Lehotzky A, Olah J, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M J Med Chem. 2016 Jan 7. PMID:26696402<ref>PMID:26696402</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5dy4" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Einsle O]]
[[Category: Gerhardt S]]
[[Category: Jung M]]
[[Category: Rumpf T]]