5G0I: Crystal Structure Of Danio Rerio Hdac6 Cd1 And Cd2 (linker Cleaved) In Complex With Nexturastat A

Citation:
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 alpha-helix and a flexible tryptophan residue in the loop joining alpha-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 alpha-tubulin lysine 40 in the lumen of microtubules, but that its preferred substrate was unpolymerized tubulin.
PDB ID: 5G0IDownload
MMDB ID: 141330
PDB Deposition Date: 2016/3/18
Updated in MMDB: 2016/10
Experimental Method:
x-ray diffraction
Resolution: 1.99  Å
Source Organism:
Similar Structures:
Biological Unit for 5G0I: monomeric; determined by author and by software (PISA)
Molecular Components in 5G0I
Label Count Molecule
Protein (1 molecule)
1
Hdac6
Molecule annotation
Chemicals (10 molecules)
1
2
2
4
3
2
4
1
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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