2v5x
From Proteopedia
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'''CRYSTAL STRUCTURE OF HDAC8-INHIBITOR COMPLEX''' | '''CRYSTAL STRUCTURE OF HDAC8-INHIBITOR COMPLEX''' | ||
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[[Category: Vannini, A.]] | [[Category: Vannini, A.]] | ||
[[Category: Volpari, C.]] | [[Category: Volpari, C.]] | ||
| - | [[Category: | + | [[Category: Alternative splicing]] |
| - | [[Category: | + | [[Category: Chromatin]] |
| - | [[Category: | + | [[Category: Chromatin regulator]] |
| - | [[Category: | + | [[Category: Deacetylation]] |
| - | [[Category: | + | [[Category: Drug design]] |
| - | [[Category: | + | [[Category: Hdac]] |
| - | [[Category: | + | [[Category: Hdac8]] |
| - | [[Category: | + | [[Category: Histone deacetylase]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[Category: Hydroxamate inhibitor]] |
| - | [[Category: | + | [[Category: Nuclear protein]] |
| - | [[Category: | + | [[Category: Nucleus]] |
| - | [[Category: | + | [[Category: P53]] |
| - | [[Category: | + | [[Category: Peptidic substrate]] |
| - | [[Category: | + | [[Category: Repressor]] |
| - | [[Category: | + | [[Category: Transcription]] |
| - | [[Category: | + | [[Category: Transcription regulation]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 18:14:08 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 15:14, 4 May 2008
CRYSTAL STRUCTURE OF HDAC8-INHIBITOR COMPLEX
Overview
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.
About this Structure
2V5X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8-substrate complex., Vannini A, Volpari C, Gallinari P, Jones P, Mattu M, Carfi A, De Francesco R, Steinkuhler C, Di Marco S, EMBO Rep. 2007 Sep;8(9):879-84. Epub 2007 Aug 10. PMID:17721440 Page seeded by OCA on Sun May 4 18:14:08 2008
Categories: Homo sapiens | Single protein | Carfi, A. | Defrancesco, R. | Gallinari, P. | Jones, P. | Marco, S Di. | Mattu, M. | Steinkuhler, C. | Vannini, A. | Volpari, C. | Alternative splicing | Chromatin | Chromatin regulator | Deacetylation | Drug design | Hdac | Hdac8 | Histone deacetylase | Hydrolase | Hydroxamate inhibitor | Nuclear protein | Nucleus | P53 | Peptidic substrate | Repressor | Transcription | Transcription regulation
