View source for 6hsg


==Crystal structure of Schistosoma mansoni HDAC8 H292M mutant complexed with NCC-149==
<StructureSection load='6hsg' size='340' side='right' caption='[[6hsg]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hsg]] 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=6HSG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HSG 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=GM5:~{N}-oxidanyl-3-[1-(phenylsulfanylmethyl)-1,2,3-triazol-4-yl]benzamide'>GM5</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HDAC8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6183 Blood fluke])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </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=6hsg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hsg OCA], [http://pdbe.org/6hsg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hsg RCSB], [http://www.ebi.ac.uk/pdbsum/6hsg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hsg ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet, the currently FDA-approved HDAC inhibitors non-specifically target at least several of the eleven structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.

Characterization of histone deacetylase 8 (HDAC8) selective inhibition reveals specific active site structural and functional determinants.,Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos Morales E, Da Veiga C, Kalinin DV, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce R, Jung M, Sippl W, Romier C J Med Chem. 2018 Oct 22. doi: 10.1021/acs.jmedchem.8b01087. PMID:30347148<ref>PMID:30347148</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6hsg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Blood fluke]]
[[Category: Histone deacetylase]]
[[Category: Marek, M]]
[[Category: Romier, C]]
[[Category: Shaik, T B]]
[[Category: Epigenetic]]
[[Category: Hdac8]]
[[Category: Hydrolase]]
[[Category: Pathogen]]
[[Category: Selective inhibitor]]