Crystal structures histone deacetylases

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

Crystal structures of a histone deacetylase-like protein (HDLP) and HDAC8 have confirmed a general pharmacophore model for HDAC inhibitors, comprising a cap joined by a hydrophobic linker to a zinc-binding group (ZBG). This model is exemplified by SAHA and the natural product HDACi Trichostatin A (TSA) 2. 

The crystal structure of FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188), a baderial class II HDAC homolog. 

R., Gallinari, P. et al. (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDACS, complexed with a hydroxamic acid inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 101 (42), 15064-15069. 

Nielsen, T.K., Hildmann, C., Dickmanns, A., Schwienhorst, A. and Ficner, R. (2005) Crystal structure of a bacterial class 2 histone deacetylase homologue. Journal of Molecular Biology, 354 (1), 107-120. 

Vannini, A., Volpari, C., Gallinari, P Jones, P., Mattu, M., Carfi, A., De Francesco, R., Steinkuhler, C. and Di Marco, S. (2007) Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex. EMBO Reports, 8 (9), 879-884. 

Guo L et al (2007) Crystal structure of a conserved N-terminal domain of histone deacetylase 4 reveals functional insights into glutamine-rich domains. Proc Natl Acad Sci USA 104(11) 4297-4302... 

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