Letters to Nature

Nature 401, 188-193 (9 September 1999) | doi:10.1038/43710; Received 14 June 1999; Accepted 30 July 1999

Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors

Michael S. Finnin1, Jill R. Donigian2, Alona Cohen2, Victoria M. Richon3, Richard A. Rifkind3, Paul A. Marks3, Ronald Breslow4 & Nikola P. Pavletich1

  1. Cellular Biochemistry and Biophsyics Program and
  2. Howard Hughes Medical Institute, Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
  3. Department of Chemistry, Columbia University, New York, New York 10027, USA

Correspondence to: Nikola P. Pavletich1 Correspondence and requests for materials should be addressed to N.P.P. (e-mail: Email: nikola@xray2.mskcc.org). Coordinates have been deposited with the Brookhaven Protein Data Bank (accession numbers 1C3P, 1C3R and 1C3S for HDLP, HDLP-Zn-TSA and HDLP-Zn-SAHA, respectively).

Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression1. HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers2, 3. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth4, 5, 6, induce terminal differentiation4, 5 and prevent the formation of tumours in mice models7, 8, and they are effective in the treatment of promyelocytic leukemia3. Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 35.2% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase–TSA and deacetylase–SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp–His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as anti-tumour agents.