2V5W
Crystal structure of HDAC8-substrate complex
Summary for 2V5W
| Entry DOI | 10.2210/pdb2v5w/pdb |
| Related | 2V5X |
| Descriptor | HISTONE DEACETYLASE 8, GLYCYL-GLYCYL-GLYCINE, PEPTIDIC SUBSTRATE, ... (6 entities in total) |
| Functional Keywords | histone deacetylase, chromatin regulator, p53, hdac, hdac8, nucleus, repressor, hydrolase, nuclear protein, peptidic substrate, transcription regulation, chromatin, transcription, deacetylation, hydrolase-hydrolase substrate complex, hydrolase/hydrolase substrate |
| Biological source | HOMO SAPIENS (HUMAN) More |
| Total number of polymer chains | 5 |
| Total formula weight | 88468.22 |
| Authors | Di Marco, S.,Vannini, A.,Volpari, C. (deposition date: 2007-07-10, release date: 2007-09-04, Last modification date: 2024-10-23) |
| 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 Cited by 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: 17721440DOI: 10.1038/SJ.EMBOR.7401047 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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