6ce6: Difference between revisions
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==Structure of HDAC6 zinc-finger ubiquitin binding domain soaked with 3,3'-(benzo[1,2-d:5,4-d']bis(thiazole)-2,6-diyl)dipropionic acid== | ==Structure of HDAC6 zinc-finger ubiquitin binding domain soaked with 3,3'-(benzo[1,2-d:5,4-d']bis(thiazole)-2,6-diyl)dipropionic acid== | ||
<StructureSection load='6ce6' size='340' side='right' caption='[[6ce6]], [[Resolution|resolution]] 1.60Å' scene=''> | <StructureSection load='6ce6' size='340' side='right'caption='[[6ce6]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6ce6]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6ce6]] is a 1 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=6CE6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CE6 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EYP:3,3-(benzo[1,2-d 5,4-d]bis[1,3]thiazole-2,6-diyl)dipropanoic+acid'>EYP</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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]] 1.6Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EYP:3,3-(benzo[1,2-d 5,4-d]bis[1,3]thiazole-2,6-diyl)dipropanoic+acid'>EYP</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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=6ce6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ce6 OCA], [https://pdbe.org/6ce6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ce6 RCSB], [https://www.ebi.ac.uk/pdbsum/6ce6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ce6 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/HDAC6_HUMAN HDAC6_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 (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin.<ref>PMID:12024216</ref> <ref>PMID:17846173</ref> In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.<ref>PMID:12024216</ref> <ref>PMID:17846173</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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==See Also== | ==See Also== | ||
*[[Hemagglutinin|Hemagglutinin]] | *[[Hemagglutinin 3D structures|Hemagglutinin 3D structures]] | ||
*[[Histone deacetylase|Histone deacetylase]] | *[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Arrowsmith | [[Category: Arrowsmith CM]] | ||
[[Category: Bountra | [[Category: Bountra C]] | ||
[[Category: Edwards | [[Category: Edwards AM]] | ||
[[Category: Freitas | [[Category: Ferreira de Freitas R]] | ||
[[Category: Halabelian | [[Category: Halabelian L]] | ||
[[Category: Harding | [[Category: Harding RJ]] | ||
[[Category: Ravichandran | [[Category: Ravichandran M]] | ||
[[Category: Santhakumar V]] | |||
[[Category: Santhakumar | [[Category: Schapira M]] | ||
[[Category: Schapira | |||
Latest revision as of 18:02, 4 October 2023
Structure of HDAC6 zinc-finger ubiquitin binding domain soaked with 3,3'-(benzo[1,2-d:5,4-d']bis(thiazole)-2,6-diyl)dipropionic acidStructure of HDAC6 zinc-finger ubiquitin binding domain soaked with 3,3'-(benzo[1,2-d:5,4-d']bis(thiazole)-2,6-diyl)dipropionic acid
Structural highlights
FunctionHDAC6_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 (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin.[1] [2] In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome. Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy.[3] [4] Publication Abstract from PubMedHDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases. Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors.,Ferreira de Freitas R, Harding RJ, Franzoni I, Ravichandran M, Mann MK, Ouyang H, Lautens M, Santhakumar V, Arrowsmith CH, Schapira M J Med Chem. 2018 May 9. doi: 10.1021/acs.jmedchem.8b00258. PMID:29741882[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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