6hu3: Difference between revisions
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==Crystal structure of Schistosoma mansoni HDAC8 complexed with a triazole hydroxamate inhibitor== | |||
<StructureSection load='6hu3' size='340' side='right'caption='[[6hu3]], [[Resolution|resolution]] 1.66Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6hu3]] 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=6HU3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HU3 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]] 1.655Å</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=GRZ:1-[5-chloranyl-2-(4-fluoranylphenoxy)phenyl]-~{N}-oxidanyl-1,2,3-triazole-4-carboxamide'>GRZ</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=6hu3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hu3 OCA], [https://pdbe.org/6hu3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hu3 RCSB], [https://www.ebi.ac.uk/pdbsum/6hu3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hu3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A5H660_SCHMA A5H660_SCHMA] | |||
<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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6hu3" style="background-color:#fffaf0;"></div> | ||
[[Category: Marek | |||
[[Category: Shaik | ==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]] | |||
[[Category: Shaik TB]] | |||
Latest revision as of 14:39, 24 January 2024
Crystal structure of Schistosoma mansoni HDAC8 complexed with a triazole hydroxamate inhibitorCrystal structure of Schistosoma mansoni HDAC8 complexed with a triazole hydroxamate inhibitor
Structural highlights
FunctionPublication Abstract from PubMedMetal-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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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