2V5X

Crystal structure of HDAC8-inhibitor complex

Summary for 2V5X

• Entry DOI: 10.2210/pdb2v5x/pdb
• Related: 1T64 1T67 1T69 1VKG 1W22 2V5W
• Descriptor: HISTONE DEACETYLASE 8, ZINC ION, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: hydroxamate inhibitor, chromatin regulator, histone deacetylase, p53, hdac, hdac8, nucleus, hydrolase, repressor, chromatin, drug design, deacetylation, transcription, transcription regulation, nuclear protein, peptidic substrate
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 87940.59

Authors

Di Marco, S.,Vannini, A.,Volpari, C.,Gallinari, P.,Jones, P.,Mattu, M.,Carfi, A.,Defrancesco, R.,Steinkuhler, C. (deposition date: 2007-07-10, release date: 2007-09-04, Last modification date: 2023-12-13)

Primary citation

Vannini, A.,Volpari, C.,Gallinari, P.,Jones, P.,Mattu, M.,Carfi, A.,Defrancesco, R.,Steinkuhler, C.,Di Marco, S.
Substrate Binding to Histone Deacetylases as Revealed by Crystal Structure of Hdac8-Substrate Complex
Embo Rep., 8:879-, 2007

PubMed 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.

PubMed: 17721440
DOI: 10.1038/SJ.EMBOR.7401047

Experimental method

X-RAY DIFFRACTION (2.25 Å)