10ai | pdb_000010ai

Crystal structure of Danio rerio histone deacetylase 6 catalytic domain 2 N530D mutant complexed with cis-BAS-2

spinqualitylabelsall models 10ai, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 10ai is a 2 chain structure with sequence from Danio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: A1C4P, EDO, K, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A7YT55_DANRE 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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