Structural biology of human metal-dependent histone deacetylases

Class I, II, and IV histone deacetylases (HDACs) are metal-dependent enzymes involved in a broad and partly unexplored array of biological mechanisms that include epigenetic control of gene expression. The catalytic domain of human classes I and IIa enzymes has been solved in complex with a substrate peptide and inhibitors, which revealed a conserved architecture, uncovered the catalytic mechanism of deacetylation, and outlined a chemical framework for inhibitor design. We will review the different structural elements of metal-dependent HDACs and their contributions to substrate recognition, catalysis, and inhibitor specificity.