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

Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression(1). HDACs are involved in cell-cycle progression and differentiation, and their deregulation is as sociated with several cancers(2,3). HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects , as they can inhibit cell. growth(4-6), induce terminal differentiation(4, 5) and prevent the formation of tumours in mice models(7,8), and they are e ffective in the treatment of promyelocytic leukemia(3). Here we describe th e structure of the histone deacetylase catalytic core, as revealed by the c rystal structure of a homologue from the hyperthermophilic bacterium Aquife x aeolieus, that shares 35.2% identity with human HDACl over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacet ylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active sit e consisting of a tubular pocket, a zinc-binding site and two Asp-His charg e-relay systems, and establish the mechanism of HDAC inhibition. The residu es that make up the active site and contact the inhibitors are conserved ac ross the HDAC family. These structures also suggest a mechanism for the dea cetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents.