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PDBsum entry 1vkg
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural snapshots of human hdac8 provide insights into the class i histone deacetylases.
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Authors
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J.R.Somoza,
R.J.Skene,
B.A.Katz,
C.Mol,
J.D.Ho,
A.J.Jennings,
C.Luong,
A.Arvai,
J.J.Buggy,
E.Chi,
J.Tang,
B.C.Sang,
E.Verner,
R.Wynands,
E.M.Leahy,
D.R.Dougan,
G.Snell,
M.Navre,
M.W.Knuth,
R.V.Swanson,
D.E.Mcree,
L.W.Tari.
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Ref.
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Structure, 2004,
12,
1325-1334.
[DOI no: ]
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PubMed id
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Abstract
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Modulation of the acetylation state of histones plays a pivotal role in the
regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal
of acetyl groups from lysines near the N termini of histones. This reaction
promotes the condensation of chromatin, leading to repression of transcription.
HDAC deregulation has been linked to several types of cancer, suggesting a
potential use for HDAC inhibitors in oncology. Here we describe the first
crystal structures of a human HDAC: the structures of human HDAC8 complexed with
four structurally diverse hydroxamate inhibitors. This work sheds light on the
catalytic mechanism of the HDACs, and on differences in substrate specificity
across the HDAC family. The structure also suggests how phosphorylation of Ser39
affects HDAC8 activity.
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Figure 3.
Figure 3. Interactions of HDAC8 with Inhibitors and
Substrate(A) Stereo figure showing key residues in the HDAC8
active site, two TSA molecules (blue and pink), the zinc
(orange), and the sodium (purple). Potential hydrogen bonds are
depicted as dashed lines.(B) F[o] - F[c] simulated annealing
omit maps showing the electron density for the two molecules of
TSA. The maps were contoured at 2.5s and are shown within 1.8 Å
of the TSA molecules.(C) Schematic diagram showing the binding
of the hydroxamate inhibitors to HDAC8.(D) Schematic diagram
showing the proposed model of how the acetylated lysine would
interact with the HDAC catalytic machinery.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2004,
12,
1325-1334)
copyright 2004.
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