2v5w
From Proteopedia
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | Histone deacetylases (HDACs)-an enzyme family that deacetylates histones | + | 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== | ==About this Structure== | ||
| Line 17: | Line 17: | ||
[[Category: Gallinari, P.]] | [[Category: Gallinari, P.]] | ||
[[Category: Jones, P.]] | [[Category: Jones, P.]] | ||
| - | [[Category: Marco, S | + | [[Category: Marco, S Di.]] |
[[Category: Mattu, M.]] | [[Category: Mattu, M.]] | ||
[[Category: Steinkuhler, C.]] | [[Category: Steinkuhler, C.]] | ||
| Line 42: | Line 42: | ||
[[Category: transcription regulation]] | [[Category: transcription regulation]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:53:21 2008'' |
Revision as of 16:53, 21 February 2008
|
CRYSTAL STRUCTURE OF HDAC8-SUBSTRATE 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
2V5W is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Known structural/functional Site: . 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 Thu Feb 21 18:53:21 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. | ACE | K | MCM | ZN | Alternative splicing | Chromatin | Chromatin regulator | Deacetylation | Hdac | Hdac8 | Histone deacetylase | Hydrolase | Nuclear protein | Nucleus | P53 | Peptidic substrate | Repressor | Transcription | Transcription regulation
