4bz6 - Revision history

OCA at 12:00, 20 December 2023

2023-12-20T12:00:38Z

←Older revision		Revision as of 12:00, 20 December 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SHH:OCTANEDIOIC+ACID+HYDROXYAMIDE+PHENYLAMIDE'>SHH</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]] 2Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SHH:OCTANEDIOIC+ACID+HYDROXYAMIDE+PHENYLAMIDE'>SHH</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=4bz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz6 OCA], [https://pdbe.org/4bz6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bz6 RCSB], [https://www.ebi.ac.uk/pdbsum/4bz6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bz6 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=4bz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz6 OCA], [https://pdbe.org/4bz6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bz6 RCSB], [https://www.ebi.ac.uk/pdbsum/4bz6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bz6 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/A5H660_SCHMA A5H660_SCHMA]]	+	[https://www.uniprot.org/uniprot/A5H660_SCHMA A5H660_SCHMA]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical alpha/beta HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens.
		+
		+	Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke,Marek M, Kannan S, Hauser AT, Moraes Mourao M, Caby S, Cura V, Stolfa DA, Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W, Jung M, Cavarelli J, Pierce RJ, Romier C PLoS Pathog. 2013 Sep;9(9):e1003645. Epub 2013 Sep 26. PMID:24086136<ref>PMID:24086136</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 4bz6" 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>

OCA at 17:17, 7 September 2022

2022-09-07T17:17:10Z

←Older revision		Revision as of 17:17, 7 September 2022
Line 3:		Line 3:
	<StructureSection load='4bz6' size='340' side='right'caption='[[4bz6]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4bz6' size='340' side='right'caption='[[4bz6]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Blood_fluke Blood fluke~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SHH:OCTANEDIOIC+ACID+HYDROXYAMIDE+PHENYLAMIDE'>SHH</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" id="ligandDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SHH:OCTANEDIOIC+ACID+HYDROXYAMIDE+PHENYLAMIDE'>SHH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bz5\|4bz5]], [[4bz7\|4bz7]], [[4bz8\|4bz8]], [[4bz9\|4bz9]]~~</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=4bz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz6 OCA], [https://pdbe.org/4bz6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bz6 RCSB], [https://www.ebi.ac.uk/pdbsum/4bz6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bz6 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=4bz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz6 OCA], [~~http~~://pdbe.org/4bz6 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4bz6 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4bz6 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4bz6 ProSAT]</span></td></tr>	+
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[[https://www.uniprot.org/uniprot/A5H660_SCHMA A5H660_SCHMA]]
-	The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical alpha/beta HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens.	+
-		+
-	Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke,Marek M, Kannan S, Hauser AT, Moraes Mourao M, Caby S, Cura V, Stolfa DA, Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W, Jung M, Cavarelli J, Pierce RJ, Romier C PLoS Pathog. 2013 Sep;9(9):~~e1003645. Epub 2013 Sep 26. PMID:24086136<ref>PMID:24086136<~~/~~ref>~~	+
-		+
-	~~From MEDLINE®~~/~~PubMed®, a database of the U~~.S. ~~National Library of Medicine.<br>~~	+
-	</~~div>~~	+
-	~~<div class="pdbe-citations 4bz6" style="background-color:#fffaf0;"><~~/~~div>~~	+

	==See Also==		==See Also==
-	*[[Histone deacetylase\|Histone deacetylase]]	+	*[[Histone deacetylase 3D structures\|Histone deacetylase 3D structures]]
-	~~== References ==~~	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Blood fluke]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Marek, M~~]]	+	[[Category: Schistosoma mansoni]]
-	[[Category: ~~Romier, C~~]]	+	[[Category: Marek M]]
-	[[Category: ~~Hydrolase]]~~	+	[[Category: Romier C]]
-	~~[[Category: Inhibition]]~~	+
-	~~[[Category: Platyhelminth~~]]	+

OCA at 13:31, 13 March 2019

2019-03-13T13:31:09Z

←Older revision		Revision as of 13:31, 13 March 2019
Line 1:		Line 1:

	==Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA==		==Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA==
-	<StructureSection load='4bz6' size='340' side='right' caption='[[4bz6]], [[Resolution\|resolution]] 2.00Å' scene=''>	+	<StructureSection load='4bz6' size='340' side='right'caption='[[4bz6]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Blood_fluke Blood fluke]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Blood_fluke Blood fluke]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>
Line 25:		Line 25:
	</StructureSection>		</StructureSection>
	[[Category: Blood fluke]]		[[Category: Blood fluke]]
		+	[[Category: Large Structures]]
	[[Category: Marek, M]]		[[Category: Marek, M]]
	[[Category: Romier, C]]		[[Category: Romier, C]]

OCA at 10:20, 11 August 2016

2016-08-11T10:20:20Z

←Older revision		Revision as of 10:20, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA==		==Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA==
	<StructureSection load='4bz6' size='340' side='right' caption='[[4bz6]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4bz6' size='340' side='right' caption='[[4bz6]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Schistosoma_mansoni Schistosoma mansoni~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Blood_fluke Blood fluke]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SHH:OCTANEDIOIC+ACID+HYDROXYAMIDE+PHENYLAMIDE'>SHH</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=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SHH:OCTANEDIOIC+ACID+HYDROXYAMIDE+PHENYLAMIDE'>SHH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bz5\|4bz5]], [[4bz7\|4bz7]], [[4bz8\|4bz8]], [[4bz9\|4bz9]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bz5\|4bz5]], [[4bz7\|4bz7]], [[4bz8\|4bz8]], [[4bz9\|4bz9]]</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=4bz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bz6 RCSB], [http://www.ebi.ac.uk/pdbsum/4bz6 PDBsum]</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=4bz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz6 OCA], [http://pdbe.org/4bz6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bz6 RCSB], [http://www.ebi.ac.uk/pdbsum/4bz6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bz6 ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 15:		Line 16:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4bz6" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 22:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Schistosoma mansoni~~]]	+	[[Category: Blood fluke]]
	[[Category: Marek, M]]		[[Category: Marek, M]]
	[[Category: Romier, C]]		[[Category: Romier, C]]

OCA at 11:32, 20 January 2015

2015-01-20T11:32:28Z

←Older revision		Revision as of 11:32, 20 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_4bz6\| PDB=4bz6 \| SCENE= }}~~	+	==Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA==
-	===Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA===	+	<StructureSection load='4bz6' size='340' side='right' caption='[[4bz6]], [[Resolution\|resolution]] 2.00Å' scene=''>
-	~~{{ABSTRACT_PUBMED_24086136}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BZ6 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SHH:OCTANEDIOIC+ACID+HYDROXYAMIDE+PHENYLAMIDE'>SHH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4bz5\|4bz5]], [[4bz7\|4bz7]], [[4bz8\|4bz8]], [[4bz9\|4bz9]]</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=4bz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bz6 RCSB], [http://www.ebi.ac.uk/pdbsum/4bz6 PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical alpha/beta HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens.

-	~~==About this Structure==~~	+	Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke,Marek M, Kannan S, Hauser AT, Moraes Mourao M, Caby S, Cura V, Stolfa DA, Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W, Jung M, Cavarelli J, Pierce RJ, Romier C PLoS Pathog. 2013 Sep;9(9):e1003645. Epub 2013 Sep 26. PMID:24086136<ref>PMID:24086136</ref>
-	~~[[4bz6]] is~~ a ~~4 chain structure with sequence from [http~~:~~//en~~.~~wikipedia~~.~~org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http~~:/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA].~~	+

-	==~~Reference~~==	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~<ref group~~=~~"xtra">PMID:024086136</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	</div>
		+
		+	==See Also==
		+	*[[Histone deacetylase\|Histone deacetylase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Schistosoma mansoni]]		[[Category: Schistosoma mansoni]]
-	[[Category: Marek, M.]]	+	[[Category: Marek, M]]
-	[[Category: Romier, C.]]	+	[[Category: Romier, C]]
	[[Category: Hydrolase]]		[[Category: Hydrolase]]
	[[Category: Inhibition]]		[[Category: Inhibition]]
	[[Category: Platyhelminth]]		[[Category: Platyhelminth]]

OCA at 06:47, 16 October 2013

2013-10-16T06:47:35Z

←Older revision		Revision as of 06:47, 16 October 2013
Line 1:		Line 1:
	{{STRUCTURE_4bz6\| PDB=4bz6 \| SCENE= }}		{{STRUCTURE_4bz6\| PDB=4bz6 \| SCENE= }}
	===Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA===		===Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA===
		+	{{ABSTRACT_PUBMED_24086136}}

	==About this Structure==		==About this Structure==
	[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA].		[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:024086136</ref><references group="xtra"/><references/>
	[[Category: Schistosoma mansoni]]		[[Category: Schistosoma mansoni]]
	[[Category: Marek, M.]]		[[Category: Marek, M.]]

OCA at 07:58, 14 August 2013

2013-08-14T07:58:02Z

←Older revision		Revision as of 07:58, 14 August 2013
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-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4bz6\| PDB=4bz6 \| SCENE= }}
		+	===Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA===

-	~~The entry~~ 4bz6 is ~~ON HOLD until Paper Publication~~	+	==About this Structure==
-		+	[[4bz6]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BZ6 OCA].
-	~~Authors~~: Marek, M., Romier, C.	+	[[Category: Schistosoma mansoni]]
-		+	[[Category: Marek, M.]]
-	~~Description~~: ~~Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA~~	+	[[Category: Romier, C.]]
		+	[[Category: Hydrolase]]
		+	[[Category: Inhibition]]
		+	[[Category: Platyhelminth]]

OCA at 19:43, 7 August 2013

2013-08-07T19:43:10Z

←Older revision		Revision as of 19:43, 7 August 2013
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4bz6 is ON HOLD	+	The entry 4bz6 is ON HOLD until Paper Publication

	Authors: Marek, M., Romier, C.		Authors: Marek, M., Romier, C.

	Description: Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA		Description: Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA

OCA: Protected "4bz6" [edit=sysop:move=sysop]

2013-08-01T04:00:37Z

Protected "4bz6" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:00, 1 August 2013

OCA: New page: '''Unreleased structure''' The entry 4bz6 is ON HOLD Authors: Marek, M., Romier, C. Description: Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA

2013-08-01T04:00:36Z

New page: '''Unreleased structure''' The entry 4bz6 is ON HOLD Authors: Marek, M., Romier, C. Description: Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA

New page

'''Unreleased structure'''

The entry 4bz6 is ON HOLD

Authors: Marek, M., Romier, C.

Description: Crystal structure of Schistosoma mansoni HDAC8 complexed with SAHA