8owz

From Proteopedia

(Difference between revisions)

Revision as of 07:39, 15 November 2023

Crystal structure of human Sirt2 in complex with a triazole-based SirReal

Structural highlights

8owz 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 1.65Å
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

Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical in vitro assays and cell-based methods for target engagement, we identified Mz325 (33) as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of 33. In ovarian cancer cells, 33 evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation.

Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation.,Sinatra L, Vogelmann A, Friedrich F, Tararina MA, Neuwirt E, Colcerasa A, Konig P, Toy L, Yesiloglu TZ, Hilscher S, Gaitzsch L, Papenkordt N, Zhai S, Zhang L, Romier C, Einsle O, Sippl W, Schutkowski M, Gross O, Bendas G, Christianson DW, Hansen FK, Jung M, Schiedel M J Med Chem. 2023 Nov 9;66(21):14787-14814. doi: 10.1021/acs.jmedchem.3c01385. , Epub 2023 Oct 30. PMID:37902787^[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
↑ Sinatra L, Vogelmann A, Friedrich F, Tararina MA, Neuwirt E, Colcerasa A, König P, Toy L, Yesiloglu TZ, Hilscher S, Gaitzsch L, Papenkordt N, Zhai S, Zhang L, Romier C, Einsle O, Sippl W, Schutkowski M, Gross O, Bendas G, Christianson DW, Hansen FK, Jung M, Schiedel M. Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation. J Med Chem. 2023 Nov 9;66(21):14787-14814. PMID:37902787 doi:10.1021/acs.jmedchem.3c01385

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/8owz"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8owz is ON HOLD  until Paper Publication
+==Crystal structure of human Sirt2 in complex with a triazole-based SirReal==
+<StructureSection load='8owz' size='340' side='right'caption='[[8owz]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8owz]] 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=8OWZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OWZ 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]] 1.65&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KZU:2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[5-[[3-[[1-(2-methoxyethyl)-1,2,3-triazol-4-yl]methoxy]phenyl]methyl]-1,3-thiazol-2-yl]ethanamide'>KZU</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=8owz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8owz OCA], [https://pdbe.org/8owz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8owz RCSB], [https://www.ebi.ac.uk/pdbsum/8owz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8owz 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 ==
+Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical in vitro assays and cell-based methods for target engagement, we identified Mz325 (33) as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of 33. In ovarian cancer cells, 33 evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation.
-Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M.
+Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation.,Sinatra L, Vogelmann A, Friedrich F, Tararina MA, Neuwirt E, Colcerasa A, Konig P, Toy L, Yesiloglu TZ, Hilscher S, Gaitzsch L, Papenkordt N, Zhai S, Zhang L, Romier C, Einsle O, Sippl W, Schutkowski M, Gross O, Bendas G, Christianson DW, Hansen FK, Jung M, Schiedel M J Med Chem. 2023 Nov 9;66(21):14787-14814. doi: 10.1021/acs.jmedchem.3c01385. , Epub 2023 Oct 30. PMID:37902787<ref>PMID:37902787</ref>
-Description: Crystal structure of human Sirt2 in complex with a triazole-based SirReal
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Friedrich, F]]
+<div class="pdbe-citations 8owz" style="background-color:#fffaf0;"></div>
-[[Category: Zhang, L]]
+== References ==
-[[Category: Jung, M]]
+<references/>
-[[Category: Schiedel, M]]
+__TOC__
-[[Category: Einsle, O]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Einsle O]]
+[[Category: Friedrich F]]
+[[Category: Jung M]]
+[[Category: Schiedel M]]
+[[Category: Zhang L]]

8owz

From Proteopedia

Revision as of 07:39, 15 November 2023

Crystal structure of human Sirt2 in complex with a triazole-based SirReal

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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