View source for 4cqf


==Crystal structure of Schistosoma mansoni HDAC8 complexed with a mercaptoacetamide inhibitor==
<StructureSection load='4cqf' size='340' side='right'caption='[[4cqf]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cqf]] 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=4CQF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CQF 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]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9Z8:6-(2-MERCAPTOACETYLAMINO)-N-PHENYLHEXANAMIDE'>9Z8</scene>, <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=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=4cqf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cqf OCA], [https://pdbe.org/4cqf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cqf RCSB], [https://www.ebi.ac.uk/pdbsum/4cqf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cqf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A5H660_SCHMA A5H660_SCHMA] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Schistosomiasis, caused by the parasitic flatworm Schistosoma mansoni and related species, is a tropical disease that affects over 200 million people worldwide. A new approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during the life cycle of the parasite. Recently, we identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for anti-parasitic therapy. Here we present results on the investigations of a focused set of HDAC inhibitors on smHDAC8. Besides several active hydroxamates, we identified a thiol based inhibitor that inhibited smHDAC8 activity in the micromolar range with unexpected selectivity over the human isotype, which has not been observed so far. The crystal structure of smHDAC8 complexed with the thiol derivative revealed that the inhibitor is accommodated in the catalytic pocket, where it interacts with both the catalytic zinc ion and the essential catalytic tyrosine (Y341) residue via its mercaptoacetamide warhead. To our knowledge, this is the first complex crystal structure of any HDAC inhibited by a mercaptoacetamide inhibitor, and therefore this finding offers a rationale for further improvement. Finally, an ester prodrug of the thiol HDAC inhibitor exhibited anti-parasitic activity on cultured schistosomes in a dose-dependent manner.

Molecular basis for the anti-parasitic activity of a mercaptoacetamide derivative that inhibits histone deacetylase 8 (HDAC8) from the human pathogen Schistosoma mansoni.,Stolfa DA, Marek M, Lancelot J, Hauser AT, Walter A, Leproult E, Melesina J, Rumpf T, Wurtz JM, Cavarelli J, Sippl W, Pierce RJ, Romier C, Jung M J Mol Biol. 2014 Mar 20. pii: S0022-2836(14)00131-4. doi:, 10.1016/j.jmb.2014.03.007. PMID:24657767<ref>PMID:24657767</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4cqf" style="background-color:#fffaf0;"></div>

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