View source for 10ai


==Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 N530D mutant complexed with cis-BAS-2==
<StructureSection load='10ai' size='340' side='right'caption='[[10ai]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[10ai]] is a 2 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=10AI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=10AI 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]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1C4P:1-morpholin-4-yl-2-sulfanyl-ethanone'>A1C4P</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=10ai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=10ai OCA], [https://pdbe.org/10ai PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=10ai RCSB], [https://www.ebi.ac.uk/pdbsum/10ai PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=10ai ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A7YT55_DANRE A7YT55_DANRE] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that deacetylates non-histone substrates such as alpha-tubulin and cortactin. HDAC6 contains two catalytic domains, each containing a catalytic zinc ion, and a zinc-finger ubiquitin-binding domain. We have discovered BAS-2, a selective HDAC6 inhibitor with an isothiouronium core and no obvious zinc-binding group. To define its mechanism, we combine X-ray crystallography, structure-activity-relationships, molecular modeling and mutagenesis. BAS-2 potently inhibits human HDAC6 but it does not inhibit zebrafish HDAC6. Computational modeling highlighted Asp567 in human HDAC6 as critical for BAS-2 recognition and mutational analyses confirmed this. The corresponding zebrafish residue is Asn530 and the crystal structure of the N530D variant zHDAC6 revealed binding of a BAS-2-derived mercaptoacetamide that engages the catalytic zinc via strong thiolate-zinc coordination. Leveraging the orientation of BAS-2 binding, we designed a BAS-2-based proteolysis targeting chimera that induced proteasome-dependent HDAC6 degradation in cells, verified by global proteomics. Collectively, these insights clarify species selectivity and demonstrate that BAS-2 acts as a selective, mechanism-based inhibitor of human HDAC6. These discoveries will aid the development of the next generation of selective HDAC6 inhibitors and degraders.

Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor.,Rodrigues DA, Wang Y, Goulart Stollmaier J, Sullivan GP, D'Arcy C, Coughlan AY, Roe A, Biro L, Watson PR, Osko JD, Twamley B, Wynne K, Cagney G, Buglyo P, Liu Y, Griffith DM, Christianson DW, Chonghaile TN Nat Commun. 2026 Jun 5. doi: 10.1038/s41467-026-73146-5. PMID:42248829<ref>PMID:42248829</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 10ai" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Danio rerio]]
[[Category: Large Structures]]
[[Category: Christianson DW]]
[[Category: Goulart Stollmaier J]]