8owz - Revision history

OCA at 11:11, 22 November 2023

OCA — Wed, 22 Nov 2023 11:11:47 GMT

←Older revision		Revision as of 11:11, 22 November 2023
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]] 1.65Å' 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]] 1.65Å</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®/PubMed®, 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]]

OCA: Replacing page with ''''Unreleased structure''' The entry 8owz is ON HOLD until Paper Publication Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M. Description: Crystal stru...'

OCA — Wed, 22 Nov 2023 05:36:38 GMT

Replacing page with ''''Unreleased structure''' The entry 8owz is ON HOLD until Paper Publication Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M. Description: Crystal stru...'

←Older revision		Revision as of 05:36, 22 November 2023
Line 1:		Line 1:
		+	'''Unreleased structure'''

-	~~==Crystal structure of human Sirt2 in complex with a triazole-based SirReal==~~	+	The entry 8owz is ON HOLD until Paper Publication
-	~~<StructureSection load='~~8owz~~' size='340' side='right'caption='[[8owz]], [[Resolution\|resolution]] 1.65Å' 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]] 1.65Å</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.	+

-	~~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>~~	+	Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M.

-	~~From MEDLINE®/PubMed®,~~ a ~~database of the U.S. National Library of Medicine.<br>~~	+	Description: Crystal structure of human Sirt2 in complex with a triazole-based SirReal
-	~~</div>~~	+	[[Category: Unreleased Structures]]
-	~~<div class="pdbe~~-~~citations 8owz" style="background-color:#fffaf0;"></div>~~	+	[[Category: Friedrich, F]]
-	~~== References ==~~	+	[[Category: Zhang, L]]
-	~~<references/>~~	+	[[Category: Jung, M]]
-	~~__TOC__~~	+	[[Category: Schiedel, M]]
-	~~</StructureSection>~~	+	[[Category: Einsle, O]]
-	[[Category: ~~Homo sapiens]]~~	+
-	~~[[Category: Large~~ Structures]]	+
-	[[Category: ~~Einsle O~~]]	+
-	[[Category: ~~Friedrich F~~]]	+
-	[[Category: Jung M]]	+
-	[[Category: Schiedel M]]	+
-	[[Category: ~~Zhang L~~]]	+

OCA at 07:39, 15 November 2023

OCA — Wed, 15 Nov 2023 07:39:41 GMT

←Older revision		Revision as of 07:39, 15 November 2023
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]] 1.65Å' 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]] 1.65Å</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®/PubMed®, 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]]

OCA at 08:12, 21 June 2023

OCA — Wed, 21 Jun 2023 08:12:44 GMT

←Older revision		Revision as of 08:12, 21 June 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8owz is ON HOLD	+	The entry 8owz is ON HOLD until Paper Publication

	Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M.		Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M.

OCA: Protected "8owz" [edit=sysop:move=sysop]

OCA — Wed, 10 May 2023 05:14:39 GMT

Protected "8owz" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:14, 10 May 2023

OCA: New page: '''Unreleased structure''' The entry 8owz is ON HOLD Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M. Description: Crystal structure of human Sirt2 in complex with...

OCA — Wed, 10 May 2023 05:14:38 GMT

New page: '''Unreleased structure''' The entry 8owz is ON HOLD Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M. Description: Crystal structure of human Sirt2 in complex with...

New page

'''Unreleased structure'''

The entry 8owz is ON HOLD

Authors: Friedrich, F., Zhang, L., Schiedel, M., Einsle, O., Jung, M.

Description: Crystal structure of human Sirt2 in complex with a triazole-based SirReal
[[Category: Unreleased Structures]]
[[Category: Friedrich, F]]
[[Category: Zhang, L]]
[[Category: Jung, M]]
[[Category: Schiedel, M]]
[[Category: Einsle, O]]