• Home
  • Publications
  • Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex

Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex

Authors:

  • Vannini A.,
  • Volpari C, Gallinari P, Jones P, Mattu M, Carfí A, De Francesco R, Steinkühler C, Di Marco S

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.

  • Facebook
  • Twitter
  • LinkedIn
  • Email

Links: