View source for 7p2u


==Crystal structure of Schistosoma mansoni HDAC8 in complex with a 3-chlorophenyl-spiroindoline capped hydroxamate-based inhibitor, bound to a novel site==
<StructureSection load='7p2u' size='340' side='right'caption='[[7p2u]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7p2u]] is a 1 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=7P2U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7P2U 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4WB:5-[[(2R)-2-(3-chlorophenyl)-1-methyl-spiro[2H-indole-3,4-piperidine]-1-yl]methyl]-N-oxidanyl-thiophene-2-carboxamide'>4WB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=7p2u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7p2u OCA], [https://pdbe.org/7p2u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7p2u RCSB], [https://www.ebi.ac.uk/pdbsum/7p2u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7p2u ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A5H660_SCHMA A5H660_SCHMA] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Parasitic diseases cause significant global morbidity and mortality particularly in the poorest regions of the world. Schistosomiasis, one of the most widespread neglected tropical diseases, affects more than 200 million people worldwide. Histone deacetylase (HDAC) inhibitors are prominent epigenetic drugs that are being investigated in the treatment of several diseases, including cancers and parasitic diseases. Schistosoma mansoni HDAC8 (SmHDAC8) is highly expressed in all life cycle stages of the parasite and selective inhibition is required in order to avoid undesirable off-target effects in the host. Herein, by X-ray crystal structures of SmHDAC8-inhibitor complexes, biochemical and phenotypic studies, we found two schistosomicidal spiroindoline-derivatives binding a novel site, next to Trp198, on the enzyme surface. We determined that by acting on this site, either by mutation of the Trp198 or by compound binding, a decrease in the activity of the enzyme is achieved. Remarkably, this allosteric site differs from the human counterpart; rather, it is conserved in all Schistosoma spp., as well as Rhabidoptera and Trematoda classes, thus paving the way for the design of HDAC8-selective allosteric inhibitors with improved properties.

Crystal structures of Schistosoma mansoni histone deacetylase 8 reveal a novel binding site for allosteric inhibitors.,Saccoccia F, Pozzetti L, Gimmelli R, Butini S, Guidi A, Papoff G, Giannaccari M, Brogi S, Scognamiglio V, Gemma S, Ruberti G, Campiani G J Biol Chem. 2022 Aug 12:102375. doi: 10.1016/j.jbc.2022.102375. PMID:35970392<ref>PMID:35970392</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7p2u" 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: Campiani G]]
[[Category: Gemma S]]
[[Category: Ruberti G]]
[[Category: Saccoccia F]]