Histone deacetylase 6 structure and molecular basis of catalysis and inhibition

Histone deacetylase 6 (HDAC6) is a critical target for drug design due to 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 and CD1 and CD2 from Danio rerio HDAC6, and we correlate these structures with activity measurements using a panel of 13 different substrates. The catalytic activity of CD2 from both species exhibits broad substrate specificity, whereas that of CD1 is highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yield unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with 8 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, reveal surprising new insight regarding changes in Zn(2+) coordination and isozyme-specific inhibition.