Journal
NATURE CHEMICAL BIOLOGY
Volume 12, Issue 9, Pages 748-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.2140
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Funding
- Novartis Research Foundation
- Nakajima Foundation
- Ara Parseghian Medical Research Foundation
- National Institutes of Health [1R01NS092653]
- Warren Family Center for Drug Discovery and Development
- Department of Chemistry and Biochemisry
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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 a-helix and a flexible tryptophan residue in the loop joining a-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 a-tubulin lysine 40 in the lumen of microtubules, but that its preferred substrate was unpolymerized tubulin.
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