Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex
Articolo
Data di Pubblicazione:
2007
Citazione:
Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex / A. Vannini, C. Volpari, P. Gallinari, P. Jones, M. Mattu, A. Carfí, R. De Francesco, C. Steinkühler, S. Di Marco. - In: EMBO REPORTS. - ISSN 1469-221X. - 8:9(2007), pp. 879-884.
Abstract:
Histone deacetylases (HDACs) - an enzyme family that deacetylates histones and non-histone proteins - are implicated in human diseases such as cancer, and the first-generation of HDAC inhibitors are now in clinical trials. Here, we report the 2.0 Å Gresolution crystal structure of a catalytically inactive HDAC8 active-site mutant, Tyr306Phe, bound to an acetylated peptidic substrate. The structure clarifies the role of active-site residues in the deacetylation reaction and substrate recognition. Notably, the structure shows the unexpected role of a conserved residue at the active-site rim, Asp 101, in positioning the substrate by directly interacting with the peptidic backbone and imposing a constrained cis-conformation. A similar interaction is observed in a new hydroxamate inhibitor-HDAC8 structure that we also solved. The crucial role of Asp 101 in substrate and inhibitor recognition was confirmed by activity and binding assays of wild-type HDAC8 and Asp101Ala, Tyr306Phe and Asp101Ala/Tyr306Phe mutants.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
HDAC; acetylated substrate; mutagenesis; crystallography; drug design
Elenco autori:
A. Vannini, C. Volpari, P. Gallinari, P. Jones, M. Mattu, A. Carfí, R. De Francesco, C. Steinkühler, S. Di Marco
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