10AI
Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 N530D mutant complexed with cis-BAS-2
This is a non-PDB format compatible entry.
Summary for 10AI
| Entry DOI | 10.2210/pdb10ai/pdb |
| Descriptor | Protein deacetylase HDAC6, 1,2-ETHANEDIOL, 1-(morpholin-4-yl)-2-sulfanylethan-1-one, ... (6 entities in total) |
| Functional Keywords | hydrolase, histone deacetylase, inhibitor, metallohydrolase |
| Biological source | Danio rerio (zebrafish) |
| Total number of polymer chains | 2 |
| Total formula weight | 81306.73 |
| Authors | |
| Primary citation | Rodrigues, D.A.,Wang, Y.,Goulart Stollmaier, J.,Sullivan, G.P.,D'Arcy, C.,Coughlan, A.Y.,Roe, A.,Biro, L.,Watson, P.R.,Osko, J.D.,Twamley, B.,Wynne, K.,Cagney, G.,Buglyo, P.,Liu, Y.,Griffith, D.M.,Christianson, D.W.,Chonghaile, T.N. Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor. Nat Commun, 2026 Cited by PubMed Abstract: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that deacetylates non-histone substrates such as α-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. PubMed: 42248829DOI: 10.1038/s41467-026-73146-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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