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==Crystal structure of fragment 3-(3-(pyridin-2-ylmethoxy)quinoxalin-2-yl)propanoic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain==
==Crystal structure of fragment 3-(3-(pyridin-2-ylmethoxy)quinoxalin-2-yl)propanoic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain==
<StructureSection load='5wpb' size='340' side='right' caption='[[5wpb]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
<StructureSection load='5wpb' size='340' side='right'caption='[[5wpb]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5wpb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WPB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WPB FirstGlance]. <br>
<table><tr><td colspan='2'>[[5wpb]] 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=5WPB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WPB FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B8P:3-{3-[(pyridin-2-yl)methoxy]quinoxalin-2-yl}propanoic+acid'>B8P</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HDAC6, KIAA0901, JM21 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B8P:3-{3-[(pyridin-2-yl)methoxy]quinoxalin-2-yl}propanoic+acid'>B8P</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5wpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wpb OCA], [https://pdbe.org/5wpb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wpb RCSB], [https://www.ebi.ac.uk/pdbsum/5wpb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wpb ProSAT]</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=5wpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wpb OCA], [http://pdbe.org/5wpb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wpb RCSB], [http://www.ebi.ac.uk/pdbsum/5wpb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wpb ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://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> 
[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;">
== Publication Abstract from PubMed ==
Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain.
 
Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin.,Harding RJ, Ferreira de Freitas R, Collins P, Franzoni I, Ravichandran M, Ouyang H, Juarez-Ornelas KA, Lautens M, Schapira M, von Delft F, Santhakumar V, Arrowsmith CH J Med Chem. 2017 Nov 9;60(21):9090-9096. doi: 10.1021/acs.jmedchem.7b00933. Epub , 2017 Oct 27. PMID:29019676<ref>PMID:29019676</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5wpb" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Histone deacetylase|Histone deacetylase]]
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Histone deacetylase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Arrowsmith, C H]]
[[Category: Arrowsmith CH]]
[[Category: Bountra, C]]
[[Category: Bountra C]]
[[Category: Edwards, A M]]
[[Category: Edwards AM]]
[[Category: Franzoni, I]]
[[Category: Ferreira de Freitas R]]
[[Category: Freitas, R Ferreira de]]
[[Category: Franzoni I]]
[[Category: Harding, R J]]
[[Category: Harding RJ]]
[[Category: Lautens, M]]
[[Category: Lautens M]]
[[Category: Ravichandran, M]]
[[Category: Ravichandran M]]
[[Category: Structural genomic]]
[[Category: Santhakumar V]]
[[Category: Santhakumar, V]]
[[Category: Schapira M]]
[[Category: Schapira, M]]
[[Category: Tempel W]]
[[Category: Tempel, W]]
[[Category: Fragment screening]]
[[Category: Hdac]]
[[Category: Hdac6]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Sgc]]

Latest revision as of 17:16, 13 March 2024

Crystal structure of fragment 3-(3-(pyridin-2-ylmethoxy)quinoxalin-2-yl)propanoic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domainCrystal structure of fragment 3-(3-(pyridin-2-ylmethoxy)quinoxalin-2-yl)propanoic acid bound in the ubiquitin binding pocket of the HDAC6 zinc-finger domain

Structural highlights

5wpb is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.55Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[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]

See Also

References

  1. ↑ Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455-8. PMID:12024216 doi:http://dx.doi.org/10.1038/417455a
  2. ↑ Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007 Sep 10;178(6):1025-38. PMID:17846173 doi:10.1083/jcb.200611128
  3. ↑ Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455-8. PMID:12024216 doi:http://dx.doi.org/10.1038/417455a
  4. ↑ Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007 Sep 10;178(6):1025-38. PMID:17846173 doi:10.1083/jcb.200611128

5wpb, resolution 1.55Å

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