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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 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.

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Figure 1: The A. aeolicus HDLP has 35.2% identity to human HDAC1.
Figure 2: The histone deacetylase catalytic core belongs to the open α/β-family of folds.
Figure 3: TSA binds inside the pocket making contacts to residues at the rim, walls and bottom of the pocket.
Figure 4: SAHA binds HDLP like TSA, but its aliphatic chain and cap groups make fewer contacts.
Figure 5: The proposed catalytic mechanism for the deacetylation of acetylated lysine.


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We thank R. Huber for the A. aeolicus chromosomal DNA preparation; C. A. Hassig and S. L. Schreiber for the HDAC1-FLAG baculovirus and for helpful discussions; A. S. Mildvan and J. Thornson for advice on the reaction mechanism; and C. Murray for administrative help. Supported by the Howard Hughes Medical Institute, the NIH, the Dewitt Wallace Foundation and the Samuel and May Rudin Foundation.

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Correspondence to Nikola P. Pavletich.

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Finnin, M., Donigian, J., Cohen, A. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188–193 (1999).

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