5yql: Difference between revisions

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'''Unreleased structure'''


The entry 5yql is ON HOLD until Paper Publication
==Crystal structure of Sirt2 in complex with selective inhibitor A2I==
<StructureSection load='5yql' size='340' side='right' caption='[[5yql]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5yql]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YQL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YQL FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A2I:2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[3-(phenoxymethyl)phenyl]ethanamide'>A2I</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5yql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yql OCA], [http://pdbe.org/5yql PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yql RCSB], [http://www.ebi.ac.uk/pdbsum/5yql PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yql ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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 ==
Human sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacylase, and is implicated in human diseases including cancer. Selective small-molecule inhibitors for SIRT2 are sought as chemical tools and potential therapeutics. Here we report the X-ray crystal structure guided structure-activity relationship studies of new N-(3-(phenoxymethyl)phenyl)acetamide derivatives with SIRT2, which led to the identification of potent, selective SIRT2 inhibitors. Crystallographic analyses reveal that the new inhibitors act via inducing the formation of an enlarged hydrophobic pocket and particularly mimicking the interactions made by myristoylated-lysine substrates. The most potent inhibitor 24a could dose-dependently elevate the acetylation level of alpha-tubulin in the non-small cell lung cancer H441cells, which have a high expression level of SIRT2 as determinated by Western blotting analyses. Further cellular assays reveal that 24a restrains cell growth mainly through inhibiting cellular proliferation rather than inducing apoptosis. Moreover, 24a could suppress the migration and invasion of H441cells. These results provide an excellent basis for further development of new potent, selective, and cell active SIRT2 inhibitors as chemical tools and potential therapeutics for SIRT2-driven non-small cell lung cancers.


Authors:  
X-ray crystal structure guided discovery of new selective, substrate-mimicking sirtuin 2 inhibitors that exhibit activities against non-small cell lung cancer cells.,Yang LL, Wang HL, Zhong L, Yuan C, Liu SY, Yu ZJ, Liu S, Yan YH, Wu C, Wang Y, Wang Z, Yu Y, Chen Q, Li GB Eur J Med Chem. 2018 Jul 15;155:806-823. doi: 10.1016/j.ejmech.2018.06.041. Epub , 2018 Jun 19. PMID:29957526<ref>PMID:29957526</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 5yql" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Chen, Q]]
[[Category: Li, G]]
[[Category: Wang, H]]
[[Category: Yu, Y]]
[[Category: Complex]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Inhibitor]]
[[Category: Nad-dependent deacetylase sirtuin-2]]

Revision as of 10:50, 17 October 2018

Crystal structure of Sirt2 in complex with selective inhibitor A2ICrystal structure of Sirt2 in complex with selective inhibitor A2I

Structural highlights

5yql is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

Human sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacylase, and is implicated in human diseases including cancer. Selective small-molecule inhibitors for SIRT2 are sought as chemical tools and potential therapeutics. Here we report the X-ray crystal structure guided structure-activity relationship studies of new N-(3-(phenoxymethyl)phenyl)acetamide derivatives with SIRT2, which led to the identification of potent, selective SIRT2 inhibitors. Crystallographic analyses reveal that the new inhibitors act via inducing the formation of an enlarged hydrophobic pocket and particularly mimicking the interactions made by myristoylated-lysine substrates. The most potent inhibitor 24a could dose-dependently elevate the acetylation level of alpha-tubulin in the non-small cell lung cancer H441cells, which have a high expression level of SIRT2 as determinated by Western blotting analyses. Further cellular assays reveal that 24a restrains cell growth mainly through inhibiting cellular proliferation rather than inducing apoptosis. Moreover, 24a could suppress the migration and invasion of H441cells. These results provide an excellent basis for further development of new potent, selective, and cell active SIRT2 inhibitors as chemical tools and potential therapeutics for SIRT2-driven non-small cell lung cancers.

X-ray crystal structure guided discovery of new selective, substrate-mimicking sirtuin 2 inhibitors that exhibit activities against non-small cell lung cancer cells.,Yang LL, Wang HL, Zhong L, Yuan C, Liu SY, Yu ZJ, Liu S, Yan YH, Wu C, Wang Y, Wang Z, Yu Y, Chen Q, Li GB Eur J Med Chem. 2018 Jul 15;155:806-823. doi: 10.1016/j.ejmech.2018.06.041. Epub , 2018 Jun 19. PMID:29957526[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ Yang LL, Wang HL, Zhong L, Yuan C, Liu SY, Yu ZJ, Liu S, Yan YH, Wu C, Wang Y, Wang Z, Yu Y, Chen Q, Li GB. X-ray crystal structure guided discovery of new selective, substrate-mimicking sirtuin 2 inhibitors that exhibit activities against non-small cell lung cancer cells. Eur J Med Chem. 2018 Jul 15;155:806-823. doi: 10.1016/j.ejmech.2018.06.041. Epub , 2018 Jun 19. PMID:29957526 doi:http://dx.doi.org/10.1016/j.ejmech.2018.06.041

5yql, resolution 1.60Å

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