PUBLICATION
Structural insights into HDAC6 tubulin deacetylation and its selective inhibition
- Authors
- Miyake, Y., Keusch, J.J., Wang, L., Saito, M., Hess, D., Wang, X., Melancon, B.J., Helquist, P., Gut, H., Matthias, P.
- ID
- ZDB-PUB-160728-19
- Date
- 2016
- Source
- Nature Chemical Biology 12(9): 748-54 (Journal)
- Registered Authors
- Keywords
- Drug discovery, Enzymes, Post-translational modifications, X-ray crystallography
- MeSH Terms
-
- Acetylation/drug effects
- Animals
- Biocatalysis
- Histone Deacetylase Inhibitors/chemistry
- Histone Deacetylase Inhibitors/pharmacology*
- Histone Deacetylases/chemistry
- Histone Deacetylases/metabolism*
- Humans
- Hydroxamic Acids/chemistry
- Hydroxamic Acids/pharmacology*
- Models, Molecular
- Structure-Activity Relationship
- Tubulin/chemistry
- Tubulin/metabolism*
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors*
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/metabolism*
- PubMed
- 27454931 Full text @ Nat. Chem. Biol.
Citation
Miyake, Y., Keusch, J.J., Wang, L., Saito, M., Hess, D., Wang, X., Melancon, B.J., Helquist, P., Gut, H., Matthias, P. (2016) Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. Nature Chemical Biology. 12(9):748-54.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping