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Structural insights into HDAC6 tubulin deacetylation and its selective inhibition.
Journal article

Structural insights into HDAC6 tubulin deacetylation and its selective inhibition.

  • Miyake Y Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
  • Keusch JJ Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
  • Wang L Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
  • Saito M Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
  • Hess D Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
  • Wang X Department of Chemistry &Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
  • Melancon BJ Department of Chemistry &Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
  • Helquist P Department of Chemistry &Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
  • Gut H Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
  • Matthias P Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
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  • 2016-07-26
Published in:
  • Nature chemical biology. - 2016
Acetylation
Animals
Biocatalysis
Histone Deacetylase 6
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Hydroxamic Acids
Models, Molecular
Structure-Activity Relationship
Tubulin
Zebrafish
Zebrafish Proteins
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/17621
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