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==== | ==Human SIRT2 in complex with myristoyl thiourea inhibitor, No.13== | ||
<StructureSection load='7bos' size='340' side='right'caption='[[7bos]]' scene=''> | <StructureSection load='7bos' size='340' side='right'caption='[[7bos]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7bos]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BOS FirstGlance]. <br> | ||
</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=7bos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bos OCA], [https://pdbe.org/7bos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bos RCSB], [https://www.ebi.ac.uk/pdbsum/7bos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bos ProSAT]</span></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=F4R:N-dodecylmethanethioamide'>F4R</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=P6S:benzyl+hydrogen+carbonate'>P6S</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=7bos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bos OCA], [https://pdbe.org/7bos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bos RCSB], [https://www.ebi.ac.uk/pdbsum/7bos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bos ProSAT]</span></td></tr> | |||
</table> | </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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of chemical probes that are potent, selective, stable in serum, water-soluble, and inhibit SIRT2-mediated deacetylation and demyristoylation in cells. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics. | |||
Mechanism-based inhibitors of SIRT2: structure-activity relationship, X-ray structures, target engagement, regulation of alpha-tubulin acetylation and inhibition of breast cancer cell migration.,Nielsen AL, Rajabi N, Kudo N, Lundo K, Moreno-Yruela C, Baek M, Fontenas M, Lucidi A, Madsen AS, Yoshida M, Olsen CA RSC Chem Biol. 2021 Jan 14;2(2):612-626. doi: 10.1039/d0cb00036a. eCollection , 2021 Apr 1. PMID:34458803<ref>PMID:34458803</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7bos" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Synthetic construct]] | ||
[[Category: Kudo N]] | |||
[[Category: Minoru Y]] | |||
[[Category: Olsen CA]] | |||
Latest revision as of 18:23, 29 November 2023
Human SIRT2 in complex with myristoyl thiourea inhibitor, No.13Human SIRT2 in complex with myristoyl thiourea inhibitor, No.13
Structural highlights
FunctionSIR2_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 PubMedSirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of chemical probes that are potent, selective, stable in serum, water-soluble, and inhibit SIRT2-mediated deacetylation and demyristoylation in cells. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics. Mechanism-based inhibitors of SIRT2: structure-activity relationship, X-ray structures, target engagement, regulation of alpha-tubulin acetylation and inhibition of breast cancer cell migration.,Nielsen AL, Rajabi N, Kudo N, Lundo K, Moreno-Yruela C, Baek M, Fontenas M, Lucidi A, Madsen AS, Yoshida M, Olsen CA RSC Chem Biol. 2021 Jan 14;2(2):612-626. doi: 10.1039/d0cb00036a. eCollection , 2021 Apr 1. PMID:34458803[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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