2v5w: Difference between revisions
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==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== | ||
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[[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.]] | ||
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[[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
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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 K, ZN, ACE and MCM as ligands. Known structural/functional Site: AC1. 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
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Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- 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
