5G0I

Crystal structure of Danio rerio HDAC6 CD1 and CD2 (linker cleaved) in complex with Nexturastat A

Summary for 5G0I

• Entry DOI: 10.2210/pdb5g0i/pdb
• Related: 5G0F 5G0G 5G0H 5G0J
• Descriptor: HDAC6, ZINC ION, POTASSIUM ION, ... (7 entities in total)
• Functional Keywords: cell cycle, histone, histone deacetylase
• Biological source: DANIO RERIO (ZEBRAFISH)
• Total number of polymer chains: 2
• Total formula weight: 180794.70

Authors

Miyake, Y.,Keusch, J.J.,Wang, L.,Saito, M.,Hess, D.,Wang, X.,Melancon, B.J.,Helquist, P.,Gut, H.,Matthias, P. (deposition date: 2016-03-18, release date: 2016-07-27, Last modification date: 2024-01-10)

Primary citation

Miyake, Y.,Keusch, J.J.,Wang, L.,Saito, M.,Hess, D.,Wang, X.,Melancon, B.J.,Helquist, P.,Gut, H.,Matthias, P.
Structural Insights Into Hdac6 Tubulin Deacetylation and its Selective Inhibition
Nat.Chem.Biol., 12:748-, 2016

PubMed 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.

PubMed: 27454931
DOI: 10.1038/NCHEMBIO.2140

Experimental method

X-RAY DIFFRACTION (1.99 Å)