6hsk
From Proteopedia
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| - | ==Crystal structure of human HDAC8 complexed with Quisinostat== | + | ==Crystal structure of a human HDAC8 L6 loop mutant complexed with Quisinostat== |
| - | <StructureSection load='6hsk' size='340' side='right' caption='[[6hsk]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='6hsk' size='340' side='right'caption='[[6hsk]], [[Resolution|resolution]] 2.10Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6hsk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HSK OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6hsk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HSK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HSK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOK:2-[4-[[(1-methylindol-3-yl)methylamino]methyl]piperidin-1-yl]-~{N}-oxidanyl-pyrimidine-5-carboxamide'>GOK</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.096Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOK:2-[4-[[(1-methylindol-3-yl)methylamino]methyl]piperidin-1-yl]-~{N}-oxidanyl-pyrimidine-5-carboxamide'>GOK</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'>[ | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6hsk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hsk OCA], [https://pdbe.org/6hsk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hsk RCSB], [https://www.ebi.ac.uk/pdbsum/6hsk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hsk ProSAT]</span></td></tr> |
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/HDAC8_HUMAN HDAC8_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. May play a role in smooth muscle cell contractility.<ref>PMID:10748112</ref> <ref>PMID:10926844</ref> <ref>PMID:10922473</ref> <ref>PMID:14701748</ref> |
| + | <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> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6hsk" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: Marek | + | [[Category: Large Structures]] |
| - | [[Category: Ramos-Morales | + | [[Category: Marek M]] |
| - | [[Category: Romier | + | [[Category: Ramos-Morales E]] |
| - | [[Category: Shaik | + | [[Category: Romier C]] |
| - | + | [[Category: Shaik TB]] | |
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Current revision
Crystal structure of a human HDAC8 L6 loop mutant complexed with Quisinostat
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