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 A resolution 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.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
Vannini A,Volpari C,Gallinari P,Jones P,Mattu M,Carfí A,De Francesco R,Steinkühler C,Di Marco Sdoi
10.1038/sj.embor.7401047subject
Has Abstractpub_date
2007-09-01 00:00:00pages
879-84issue
9eissn
1469-221Xissn
1469-3178pii
7401047journal_volume
8pub_type
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