5dy5: Difference between revisions

Latest revision as of 22:05, 28 June 2023

Crystal structure of human Sirt2 in complex with a SirReal probe fragment

Structural highlights

5dy5 is a 1 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 1.95Å
Ligands:	5GR, BU3, EDO, EPE, ZN
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

Sirtuins are NAD+ -dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the epsilon-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, thus making Sirt2 a promising target for pharmaceutical intervention. Here, based on a crystal structure of Sirt2 in complex with an optimized sirtuin rearranging ligand (SirReal) that shows improved potency, water solubility, and cellular efficacy, we present the development of the first Sirt2-selective affinity probe. A slow dissociation of the probe/enzyme complex offers new applications for SirReals, such as biophysical characterization, fragment-based screening, and affinity pull-down assays. This possibility makes the SirReal probe an important tool for studying sirtuin biology.

Structure-Based Development of an Affinity Probe for Sirtuin 2.,Schiedel M, Rumpf T, Karaman B, Lehotzky A, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M Angew Chem Int Ed Engl. 2016 Jan 8. doi: 10.1002/anie.201509843. PMID:26748890^[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, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M. Structure-Based Development of an Affinity Probe for Sirtuin 2. Angew Chem Int Ed Engl. 2016 Jan 8. doi: 10.1002/anie.201509843. PMID:26748890 doi:https://dx.doi.org/10.1002/anie.201509843

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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] Schiedel M, Rumpf T, Karaman B, Lehotzky A, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M. Structure-Based Development of an Affinity Probe for Sirtuin 2. Angew Chem Int Ed Engl. 2016 Jan 8. doi: 10.1002/anie.201509843. PMID:26748890 doi:https://dx.doi.org/10.1002/anie.201509843

[1]

[2]

[3]

[4]

[5]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5dy5 is ON HOLD
+==Crystal structure of human Sirt2 in complex with a SirReal probe fragment==
+<StructureSection load='5dy5' size='340' side='right'caption='[[5dy5]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5dy5]] 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=5DY5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DY5 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]] 1.95&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5GR:N-(5-{3-[(1-BENZYL-1H-1,2,3-TRIAZOL-4-YL)METHOXY]BENZYL}-1,3-THIAZOL-2-YL)-2-[(4,6-DIMETHYLPYRIMIDIN-2-YL)SULFANYL]ACETAMIDE'>5GR</scene>, <scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</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=5dy5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dy5 OCA], [https://pdbe.org/5dy5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dy5 RCSB], [https://www.ebi.ac.uk/pdbsum/5dy5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dy5 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Sirtuins are NAD+ -dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the epsilon-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, thus making Sirt2 a promising target for pharmaceutical intervention. Here, based on a crystal structure of Sirt2 in complex with an optimized sirtuin rearranging ligand (SirReal) that shows improved potency, water solubility, and cellular efficacy, we present the development of the first Sirt2-selective affinity probe. A slow dissociation of the probe/enzyme complex offers new applications for SirReals, such as biophysical characterization, fragment-based screening, and affinity pull-down assays. This possibility makes the SirReal probe an important tool for studying sirtuin biology.
-Authors: Rumpf, T., Gerhardt, S., Einsle, O., Jung, M.
+Structure-Based Development of an Affinity Probe for Sirtuin 2.,Schiedel M, Rumpf T, Karaman B, Lehotzky A, Gerhardt S, Ovadi J, Sippl W, Einsle O, Jung M Angew Chem Int Ed Engl. 2016 Jan 8. doi: 10.1002/anie.201509843. PMID:26748890<ref>PMID:26748890</ref>
-Description: Crystal structure of human Sirt2 in complex with a SirReal probe fragment
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Rumpf, T]]
+<div class="pdbe-citations 5dy5" style="background-color:#fffaf0;"></div>
-[[Category: Gerhardt, S]]
-[[Category: Jung, M]]
+==See Also==
-[[Category: Einsle, O]]
+*[[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]]

5dy5: Difference between revisions

Latest revision as of 22:05, 28 June 2023

Crystal structure of human Sirt2 in complex with a SirReal probe fragment

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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