5dy4

From Proteopedia

(Difference between revisions)

Revision as of 20:15, 13 January 2016

Crystal structure of human Sirt2 in complex with a brominated 2nd generation SirReal inhibitor and NAD+

Structural highlights

5dy4 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

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

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^[5]

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

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
↑ Schiedel M, Rumpf T, Karaman B, Lehotzky A, Olah J, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M. Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study. J Med Chem. 2016 Jan 7. PMID:26696402 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01517

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5dy4"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==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. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DY4 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5dy4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dy4 OCA], [http://pdbe.org/5dy4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dy4 RCSB], [http://www.ebi.ac.uk/pdbsum/5dy4 PDBsum]</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 ==
+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.
-The entry 5dy4 is ON HOLD  until Paper Publication
+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>
-Authors: Rumpf, T., Gerhardt, S., Einsle, O., Jung, M.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Crystal structure of human Sirt2 in complex with a brominated 2nd generation SirReal inhibitor and NAD+
+<div class="pdbe-citations 5dy4" style="background-color:#fffaf0;"></div>
-[[Category: Unreleased Structures]]
+== References ==
-[[Category: Rumpf, T]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Einsle, O]]
 [[Category: Gerhardt, S]]
 [[Category: Jung, M]]
-[[Category: Einsle, O]]
+[[Category: Rumpf, T]]
+[[Category: Hydrolase]]
+[[Category: Hydrolase inhibitor complex]]

5dy4

From Proteopedia

Revision as of 20:15, 13 January 2016

Crystal structure of human Sirt2 in complex with a brominated 2nd generation SirReal inhibitor and NAD+

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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