Structural insights into HDAC6 tubulin deacetylation and its selective inhibition.

We report crystal structures of zebrafish histone deacetylase 6 (HDAC6) catalytic domains in tandem or as single domains in complex with the (R) and (S) enantiomers of trichostatin A (TSA) or with the HDAC6-specific inhibitor nexturastat A. The tandem domains formed, together with the inter-domain linker, an ellipsoid-shaped complex with ...
pseudo-twofold symmetry. We identified important active site differences between both catalytic domains and revealed the binding mode of HDAC6 selective inhibitors. HDAC inhibition assays with (R)- and (S)-TSA showed that (R)-TSA was a broad-range inhibitor, whereas (S)-TSA had moderate selectivity for HDAC6. We identified a uniquely positioned ?-helix and a flexible tryptophan residue in the loop joining ?-helices H20 to H21 as critical for deacetylation of the physiologic substrate tubulin. Using single-molecule measurements and biochemical assays we demonstrated that HDAC6 catalytic domain 2 deacetylated ?-tubulin lysine 40 in the lumen of microtubules, but that its preferred substrate was unpolymerized tubulin.
Mesh Terms:
Acetylation, Animals, Biocatalysis, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Models, Molecular, Structure-Activity Relationship, Tubulin, Zebrafish, Zebrafish Proteins
Nat Chem Biol
Date: Dec. 01, 2015
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