2v5x: Difference between revisions
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
==Overview== | ==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, . | 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== | ||
2V5X is a | 2V5X is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, K and V5X as [http://en.wikipedia.org/wiki/ligands ligands]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2V5X OCA]. | ||
==Reference== | ==Reference== | ||
| Line 44: | Line 44: | ||
[[Category: transcription regulation]] | [[Category: transcription regulation]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:36:23 2007'' | ||
Revision as of 13:31, 5 November 2007
|
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 with ZN, K and V5X as ligands. Structure known Active 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
Page seeded by OCA on Mon Nov 5 15:36:23 2007
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.
- K
- V5X
- ZN
- 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
