View source for 4bz9


==Crystal structure of Schistosoma mansoni HDAC8 complexed with J1075==
<StructureSection load='4bz9' size='340' side='right'caption='[[4bz9]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4bz9]] 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=4BZ9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZ9 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]] 2&#8491;</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=KMY:3-CHLOROBENZOTHIOPHENE-2-CARBOHYDROXAMIC+ACID'>KMY</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=4bz9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bz9 OCA], [https://pdbe.org/4bz9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bz9 RCSB], [https://www.ebi.ac.uk/pdbsum/4bz9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bz9 ProSAT]</span></td></tr>
</table>
== Function ==
[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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4bz9" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Schistosoma mansoni]]
[[Category: Marek M]]
[[Category: Romier C]]