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Nat Chem Biol. 2016 Sep;12(9):748-54. doi: 10.1038/nchembio.2140. Epub 2016 Jul 25.

Structural insights into HDAC6 tubulin deacetylation and its selective inhibition.

Author information

1
Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
2
Department of Chemistry &Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
3
Faculty of Sciences, University of Basel, Basel, Switzerland.

Abstract

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 α-helix and a flexible tryptophan residue in the loop joining α-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 α-tubulin lysine 40 in the lumen of microtubules, but that its preferred substrate was unpolymerized tubulin.

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PMID:
27454931
DOI:
10.1038/nchembio.2140
[Indexed for MEDLINE]

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