PDBsum entry 5g0h

Cell cycle

PDB id: 5g0h

Contents

Protein chain

360 a.a.

Ligands

E1Z

EDO ×10

Metals

__K ×2

_ZN

Waters ×353

References listed in PDB file

Key reference

• Title: Structural insights into hdac6 tubulin deacetylation and its selective inhibition.
• Authors: Y.Miyake, J.J.Keusch, L.Wang, M.Saito, D.Hess, X.Wang, B.J.Melancon, P.Helquist, H.Gut, P.Matthias.
• Ref.: Nat Chem Biol, 2016, 12, 748-754. [DOI no: 10.1038/nchembio.2140]
• PubMed id: 27454931

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.