5wgi: Difference between revisions
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==Ultrahigh resolution crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with TSA== | ==Ultrahigh resolution crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with TSA== | ||
<StructureSection load='5wgi' size='340' side='right' caption='[[5wgi]], [[Resolution|resolution]] 1.05Å' scene=''> | <StructureSection load='5wgi' size='340' side='right'caption='[[5wgi]], [[Resolution|resolution]] 1.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5wgi]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5wgi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WGI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WGI FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TSN:TRICHOSTATIN+A'>TSN</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]] 1.05Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=TSN:TRICHOSTATIN+A'>TSN</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=5wgi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wgi OCA], [https://pdbe.org/5wgi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wgi RCSB], [https://www.ebi.ac.uk/pdbsum/5wgi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wgi ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/F8W4B7_DANRE F8W4B7_DANRE] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5wgi" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5wgi" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Danio rerio]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Christianson DW]] | ||
[[Category: | [[Category: Porter NJ]] | ||
Latest revision as of 17:12, 4 October 2023
Ultrahigh resolution crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with TSAUltrahigh resolution crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 in complex with TSA
Structural highlights
FunctionPublication Abstract from PubMedHistone deacetylases (HDACs) regulate myriad cellular processes by catalyzing the hydrolysis of acetyl-l-lysine residues in histone and nonhistone proteins. The Zn(2+)-dependent class IIb enzyme HDAC6 regulates microtubule function by deacetylating alpha-tubulin, which suppresses microtubule dynamics and leads to cell cycle arrest and apoptosis. Accordingly, HDAC6 is a target for the development of selective inhibitors that might be useful in new therapeutic approaches for the treatment of cancer, neurodegenerative diseases, and other disorders. Here, we present high-resolution structures of catalytic domain 2 from Danio rerio HDAC6 (henceforth simply "HDAC6") complexed with compounds that selectively inhibit HDAC6 while maintaining nanomolar inhibitory potency: N-hydroxy-4-[(N(2-hydroxyethyl)-2-phenylacetamido)methyl)-benzamide)] (HPB), ACY-1215 (Ricolinostat), and ACY-1083. These structures reveal that an unusual monodentate Zn(2+) coordination mode is exploited by sterically bulky HDAC6-selective phenylhydroxamate inhibitors. We additionally report the ultrahigh-resolution structure of the HDAC6-trichostatin A complex, which reveals two Zn(2+)-binding conformers for the inhibitor: a major conformer (70%) with canonical bidentate hydroxamate-Zn(2+) coordination geometry and a minor conformer (30%) with monodentate hydroxamate-Zn(2+) coordination geometry, reflecting a free energy difference of only 0.5 kcal/mol. The minor conformer is not visible in lower resolution structure determinations. Structural comparisons of HDAC6-inhibitor complexes with class I HDACs suggest active site features that contribute to the isozyme selectivity observed in biochemical assays. Unusual zinc-binding mode of HDAC6-selective hydroxamate inhibitors.,Porter NJ, Mahendran A, Breslow R, Christianson DW Proc Natl Acad Sci U S A. 2017 Dec 4. pii: 1718823114. doi:, 10.1073/pnas.1718823114. PMID:29203661[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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