Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity

J Biol Chem. 2008 Apr 25;283(17):11355-63. doi: 10.1074/jbc.M707362200. Epub 2008 Feb 19.


Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Gene Expression Regulation, Enzymologic*
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Histone Deacetylases / physiology
  • Humans
  • Kinetics
  • Ligands
  • Models, Biological
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Zinc / chemistry


  • Ligands
  • HDAC7 protein, human
  • Histone Deacetylases
  • Zinc

Associated data