6css - Revision history

OCA at 14:30, 13 March 2024

2024-03-13T14:30:19Z

← Older revision		Revision as of 14:30, 13 March 2024
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	<StructureSection load='6css' size='340' side='right'caption='[[6css]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='6css' size='340' side='right'caption='[[6css]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6css]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Brachidanio_rerio Brachidanio~~ rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CSS OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6CSS FirstGlance]. <br>		<table><tr><td colspan='2'>[[6css]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CSS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CSS FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FBJ:N-hydroxycyclopent-1-ene-1-carboxamide'>FBJ</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>~~</td></tr>~~		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.7Å</td></tr>
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">hdac6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7955 Brachidanio rerio])~~</td></tr>		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FBJ:N-hydroxycyclopent-1-ene-1-carboxamide'>FBJ</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=6css FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6css OCA], [~~http~~://pdbe.org/6css PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6css RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6css PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6css ProSAT]</span></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=6css FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6css OCA], [https://pdbe.org/6css PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6css RCSB], [https://www.ebi.ac.uk/pdbsum/6css PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6css ProSAT]</span></td></tr>
	</table>		</table>
	~~<div style~~=~~"background-color:#fffaf0;">~~		== Function ==
	== ~~Publication Abstract from PubMed ==~~		[https://www.uniprot.org/uniprot/F8W4B7_DANRE F8W4B7_DANRE]
	Among the metal-dependent histone deacetylases, the class IIb isozyme HDAC6 is remarkable because of its role in the regulation of microtubule dynamics in the cytosol. Selective inhibition of HDAC6 results in microtubule hyperacetylation, leading to cell cycle arrest and apoptosis, which is a validated strategy for cancer chemotherapy and the treatment of other disorders. HDAC6 inhibitors generally consist of a Zn(2+)-binding group such as a hydroxamate, a linker, and a capping group; the capping group is a critical determinant of isozyme selectivity. Surprisingly, however, even "capless" inhibitors exhibit appreciable HDAC6 selectivity. To probe the chemical basis for this selectivity, we now report high-resolution crystal structures of HDAC6 complexed with capless cycloalkyl hydroxamate inhibitors 1-4. Each inhibitor hydroxamate group coordinates to the catalytic Zn(2+) ion with canonical bidentate geometry. Additionally, the olefin moieties of compounds 2 and 4 bind in an aromatic crevice between the side chains of F583 and F643. Reasoning that similar binding could be achieved in the representative class I isozyme HDAC8, we employed isothermal titration calorimetry to study the thermodynamics of inhibitor binding. These measurements indicate that the entropy of inhibitor binding is generally positive for binding to HDAC6 and negative for binding to HDAC8, resulting in </=313-fold selectivity for binding to HDAC6 relative to HDAC8. Thus, favorable binding entropy contributes to HDAC6 selectivity. Notably, cyclohexenyl hydroxamate 2 represents a promising lead for derivatization with capping groups that may further enhance its impressive 313-fold thermodynamic selectivity for HDAC6 inhibition.

	Entropy as a Driver of Selectivity for Inhibitor Binding to Histone Deacetylase 6.,Porter NJ, Wagner FF, Christianson DW Biochemistry. 2018 May 18. doi: 10.1021/acs.biochem.8b00367. PMID:29775292<ref>PMID:~~29775292<~~/~~ref>~~

	~~From MEDLINE®~~/~~PubMed®, a database of the U~~.S. ~~National Library of Medicine.<br>~~
	</~~div>~~
	~~<div class="pdbe-citations 6css" style="background-color:#fffaf0;"><~~/~~div>~~

	==See Also==		==See Also==
	*[[Histone deacetylase 3D structures\|Histone deacetylase 3D structures]]		*[[Histone deacetylase 3D structures\|Histone deacetylase 3D structures]]
	~~== References ==~~
	~~<references/>~~
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Brachidanio~~ rerio]]		[[Category: Danio rerio]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Christianson~~, D W~~]]		[[Category: Christianson DW]]
	[[Category: Porter~~, N J]]~~		[[Category: Porter NJ]]
	~~[[Category: Hydrolase]]~~
	~~[[Category: Tubulin deacetylase]]~~
	~~[[Category: Zinc hydrolase~~]]

OCA at 10:50, 1 January 2020

2020-01-01T10:50:25Z

← Older revision		Revision as of 10:50, 1 January 2020
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	==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with cyclopentenylhydroxamate==		==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with cyclopentenylhydroxamate==
	<StructureSection load='6css' size='340' side='right' caption='[[6css]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='6css' size='340' side='right'caption='[[6css]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6css]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Brachidanio_rerio Brachidanio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CSS FirstGlance]. <br>		<table><tr><td colspan='2'>[[6css]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Brachidanio_rerio Brachidanio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CSS FirstGlance]. <br>
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	</div>		</div>
	<div class="pdbe-citations 6css" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6css" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[Histone deacetylase 3D structures\|Histone deacetylase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
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	</StructureSection>		</StructureSection>
	[[Category: Brachidanio rerio]]		[[Category: Brachidanio rerio]]
			[[Category: Large Structures]]
	[[Category: Christianson, D W]]		[[Category: Christianson, D W]]
	[[Category: Porter, N J]]		[[Category: Porter, N J]]

OCA at 06:13, 11 July 2018

2018-07-11T06:13:30Z

← Older revision		Revision as of 06:13, 11 July 2018
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	<StructureSection load='6css' size='340' side='right' caption='[[6css]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='6css' size='340' side='right' caption='[[6css]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6css]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CSS FirstGlance]. <br>		<table><tr><td colspan='2'>[[6css]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Brachidanio_rerio Brachidanio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CSS FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FBJ:N-hydroxycyclopent-1-ene-1-carboxamide'>FBJ</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FBJ:N-hydroxycyclopent-1-ene-1-carboxamide'>FBJ</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">hdac6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7955 Brachidanio rerio])</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=6css FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6css OCA], [http://pdbe.org/6css PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6css RCSB], [http://www.ebi.ac.uk/pdbsum/6css PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6css ProSAT]</span></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=6css FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6css OCA], [http://pdbe.org/6css PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6css RCSB], [http://www.ebi.ac.uk/pdbsum/6css PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6css ProSAT]</span></td></tr>
	</table>		</table>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Brachidanio rerio]]
	[[Category: Christianson, D W]]		[[Category: Christianson, D W]]
	[[Category: Porter, N J]]		[[Category: Porter, N J]]

OCA at 05:35, 30 May 2018

2018-05-30T05:35:51Z

← Older revision		Revision as of 05:35, 30 May 2018
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry~~ 6css is ~~ON HOLD until Paper~~ Publication		==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with cyclopentenylhydroxamate==
			<StructureSection load='6css' size='340' side='right' caption='[[6css]], [[Resolution\|resolution]] 1.70Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[6css]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CSS FirstGlance]. <br>
			</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FBJ:N-hydroxycyclopent-1-ene-1-carboxamide'>FBJ</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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=6css FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6css OCA], [http://pdbe.org/6css PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6css RCSB], [http://www.ebi.ac.uk/pdbsum/6css PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6css ProSAT]</span></td></tr>
			</table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Among the metal-dependent histone deacetylases, the class IIb isozyme HDAC6 is remarkable because of its role in the regulation of microtubule dynamics in the cytosol. Selective inhibition of HDAC6 results in microtubule hyperacetylation, leading to cell cycle arrest and apoptosis, which is a validated strategy for cancer chemotherapy and the treatment of other disorders. HDAC6 inhibitors generally consist of a Zn(2+)-binding group such as a hydroxamate, a linker, and a capping group; the capping group is a critical determinant of isozyme selectivity. Surprisingly, however, even "capless" inhibitors exhibit appreciable HDAC6 selectivity. To probe the chemical basis for this selectivity, we now report high-resolution crystal structures of HDAC6 complexed with capless cycloalkyl hydroxamate inhibitors 1-4. Each inhibitor hydroxamate group coordinates to the catalytic Zn(2+) ion with canonical bidentate geometry. Additionally, the olefin moieties of compounds 2 and 4 bind in an aromatic crevice between the side chains of F583 and F643. Reasoning that similar binding could be achieved in the representative class I isozyme HDAC8, we employed isothermal titration calorimetry to study the thermodynamics of inhibitor binding. These measurements indicate that the entropy of inhibitor binding is generally positive for binding to HDAC6 and negative for binding to HDAC8, resulting in </=313-fold selectivity for binding to HDAC6 relative to HDAC8. Thus, favorable binding entropy contributes to HDAC6 selectivity. Notably, cyclohexenyl hydroxamate 2 represents a promising lead for derivatization with capping groups that may further enhance its impressive 313-fold thermodynamic selectivity for HDAC6 inhibition.

	~~Authors:~~ Porter, N.J.~~, Christianson, D~~.W.		Entropy as a Driver of Selectivity for Inhibitor Binding to Histone Deacetylase 6.,Porter NJ, Wagner FF, Christianson DW Biochemistry. 2018 May 18. doi: 10.1021/acs.biochem.8b00367. PMID:29775292<ref>PMID:29775292</ref>

	~~Description: Crystal structure~~ of ~~Danio rerio histone deacetylase 6 catalytic domain 2 in complex with cyclopentenylhydroxamate~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[Category~~: ~~Unreleased Structures]]~~		</div>
	[[Category: Christianson, D.W]]		<div class="pdbe-citations 6css" style="background-color:#fffaf0;"></div>
	[[Category: Porter, N.J]]		== References ==
			<references/>
			__TOC__
			</StructureSection>
			[[Category: Christianson, D W]]
			[[Category: Porter, N J]]
			[[Category: Hydrolase]]
			[[Category: Tubulin deacetylase]]
			[[Category: Zinc hydrolase]]

OCA at 04:01, 25 April 2018

2018-04-25T04:01:16Z

← Older revision		Revision as of 04:01, 25 April 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 6css is ON HOLD		The entry 6css is ON HOLD until Paper Publication

	Authors: Porter, N.J., Christianson, D.W.		Authors: Porter, N.J., Christianson, D.W.

OCA: Protected "6css" [edit=sysop:move=sysop]

2018-03-28T05:21:38Z

Protected "6css" [edit=sysop:move=sysop]

← Older revision	Revision as of 05:21, 28 March 2018
(No difference)

OCA: New page: '''Unreleased structure''' The entry 6css is ON HOLD Authors: Porter, N.J., Christianson, D.W. Description: Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in...

2018-03-28T05:21:37Z

New page: '''Unreleased structure''' The entry 6css is ON HOLD Authors: Porter, N.J., Christianson, D.W. Description: Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in...

New page

'''Unreleased structure'''

The entry 6css is ON HOLD

Authors: Porter, N.J., Christianson, D.W.

Description: Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with cyclopentenylhydroxamate
[[Category: Unreleased Structures]]
[[Category: Christianson, D.W]]
[[Category: Porter, N.J]]