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| | <StructureSection load='6nr0' size='340' side='right'caption='[[6nr0]], [[Resolution|resolution]] 2.45Å' scene=''> | | <StructureSection load='6nr0' size='340' side='right'caption='[[6nr0]], [[Resolution|resolution]] 2.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6nr0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NR0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NR0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6nr0]] is a 2 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=6NR0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NR0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KXG:[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]+[(3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-sulfanyl-oxolan-2-yl]methyl+hydrogen+phosphate'>KXG</scene>, <scene name='pdbligand=KXJ:N~2~-[3-(2-hydroxyethoxy)propanoyl]-N-phenyl-N~6~-tetradecanethioyl-L-lysinamide'>KXJ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.45Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SIRT2, SIR2L, SIR2L2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KXG:[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]+[(3~{S},4~{R},5~{R})-3,4-bis(oxidanyl)-5-sulfanyl-oxolan-2-yl]methyl+hydrogen+phosphate'>KXG</scene>, <scene name='pdbligand=KXJ:N~2~-[3-(2-hydroxyethoxy)propanoyl]-N-phenyl-N~6~-tetradecanethioyl-L-lysinamide'>KXJ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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'>[https://proteopedia.org/fgij/fg.htm?mol=6nr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nr0 OCA], [https://pdbe.org/6nr0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nr0 RCSB], [https://www.ebi.ac.uk/pdbsum/6nr0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nr0 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=6nr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nr0 OCA], [https://pdbe.org/6nr0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nr0 RCSB], [https://www.ebi.ac.uk/pdbsum/6nr0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nr0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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>
| + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Hong, J]] | + | [[Category: Hong J]] |
| - | [[Category: Price, I R]] | + | [[Category: Price IR]] |
| - | [[Category: Deacylase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Intermediate]]
| + | |
| Structural highlights
6nr0 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.45Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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 PubMed
Small molecule inhibitors for SIRT2, a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases, have shown promise in treating cancer and neurodegenerative diseases. Developing SIRT2-selective inhibitors with better pharmacological properties is key to further realize the therapeutic potential of targeting SIRT2. One of the best SIRT2-selective inhibitors reported is a thiomyristoyl lysine compound called TM, which showed promising anticancer activity in mouse models without much toxicity to normal cells. The main limitations of TM, however, are the low aqueous solubility and lack of X-ray crystal structures to aid future drug design. Here, we designed and synthesized a glucose-conjugated TM (glucose-TM) analog with superior aqueous solubility. Although glucose-TM is not cell permeable, the excellent aqueous solubility allowed us to obtain a crystal structure of SIRT2 in complex with it. The structure enabled us to design several new TM analogs, one of which, NH4-6, showed superior water solubility and better anticancer activity in cell culture. The results of these studies provided important insights that will further fuel the future development of improved SIRT2 inhibitors as promising therapeutics for treating cancer and neurodegeneration.
A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors.,Hong JY, Price IR, Bai JJ, Lin H ACS Chem Biol. 2019 Aug 16;14(8):1802-1810. doi: 10.1021/acschembio.9b00384. Epub, 2019 Aug 2. PMID:31373792[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. PMID:12620231
- ↑ Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003 May;23(9):3173-85. PMID:12697818
- ↑ Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci. 2010 Dec 15;123(Pt 24):4251-8. doi: 10.1242/jcs.073783. Epub 2010 Nov, 16. PMID:21081649 doi:10.1242/jcs.073783
- ↑ Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011 Jul 8;43(1):33-44. doi: 10.1016/j.molcel.2011.04.028. PMID:21726808 doi:10.1016/j.molcel.2011.04.028
- ↑ Hong JY, Price IR, Bai JJ, Lin H. A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors. ACS Chem Biol. 2019 Aug 16;14(8):1802-1810. doi: 10.1021/acschembio.9b00384. Epub, 2019 Aug 2. PMID:31373792 doi:http://dx.doi.org/10.1021/acschembio.9b00384
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