5EFK: Crystal Structure Of Danio Rerio Histone Deacetylase 6 Catalytic Domain 2 (y745f Mutant) In Complex With Alpha Tubulin K40 Tripeptide Substrate

Citation:
Abstract
Histone deacetylase 6 (HDAC6) is a critical target for drug design because of its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens HDAC6 and of CD1 and CD2 from Danio rerio HDAC6. We correlated these structures with activity measurements using 13 different substrates. The catalytic activity of CD2 from both species exhibited broad substrate specificity, whereas that of CD1 was highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yielded unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with eight different inhibitors, including belinostat and panobinostat (currently used in cancer chemotherapy), the macrocyclic tetrapeptide HC toxin, and the HDAC6-specific inhibitor N-hydroxy-4-(2-((2-hydroxyethyl)(phenyl)amino)-2-oxoethyl)benzamide, revealed surprising new insight regarding changes in Zn(2+) coordination and isozyme-specific inhibition.
PDB ID: 5EFKDownload
MMDB ID: 141303
PDB Deposition Date: 2015/10/23
Updated in MMDB: 2017/09
Experimental Method:
x-ray diffraction
Resolution: 1.82  Å
Source Organism:
Similar Structures:
Biological Unit for 5EFK: dimeric; determined by author and by software (PISA)
Molecular Components in 5EFK
Label Count Molecule
Proteins (2 molecules)
1
Hdac6 Protein
Molecule annotation
1
Alpha Tubulin K40 Tripeptide
Molecule annotation
Chemicals (8 molecules)
1
1
2
2
3
1
4
1
5
1
6
1
7
1
* Click molecule labels to explore molecular sequence information.

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