 |
PDBsum entry 3c0z
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Human hdac7 harbors a class iia histone deacetylase-Specific zinc binding motif and cryptic deacetylase activity.
|
|
|
Authors
|
|
A.Schuetz,
J.Min,
A.Allali-Hassani,
M.Schapira,
M.Shuen,
P.Loppnau,
R.Mazitschek,
N.P.Kwiatkowski,
T.A.Lewis,
R.L.Maglathin,
T.H.Mclean,
A.Bochkarev,
A.N.Plotnikov,
M.Vedadi,
C.H.Arrowsmith.
|
|
|
Ref.
|
|
J Biol Chem, 2008,
283,
11355-11363.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
Histone deacetylases (HDACs) are protein deacetylases that play a role in
repression of gene transcription and are emerging targets in cancer therapy.
Here, we characterize the structure and enzymatic activity of the catalytic
domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a
multiprotein complex, we show that cdHDAC7 has a low level of deacetylase
activity which can be inhibited by known HDAC inhibitors. The crystal structures
of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first
structures of the catalytic domain of class IIa HDACs and demonstrate
significant differences with previously reported class I and class IIb-like HDAC
structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc
binding motif adjacent to the active site which is likely to participate in
substrate recognition and protein-protein interaction and may provide a site for
modulation of activity. Furthermore, a different active site topology results in
modified catalytic properties and in an enlarged active site pocket. Our studies
provide mechanistic insights into class IIa HDACs and facilitate the design of
specific modulators.
|
|
|
|
|
|
|
|
Figure 2.
Stereo view of the cdHDAC7 active site. Shown are the
interactions in the structure of apo-cdHDAC7 (A) and in the
cdHDAC7·TSA complex structure (B). Water molecules are
shown as blue spheres and potential hydrogen bonds as blue
dashed lines.
|
|
Figure 4.
Hydroxamate inhibitor binding of cdHDAC7. A and B, the 2|F[0]
- F[c]| electron density maps for the bound zinc and inhibitor
molecules in the active site of cdHDAC7 are contoured at 0.9σ
(blue). TSA (A) and SAHA (B) are shown as stick models colored
as per atom type: carbon in green, oxygen in red, and nitrogen
in blue. C, the TSA molecule bound in the cdHDAC7 active site is
shown as a sphere model. The histidine residue His-843 points
away from the active site, resulting in an enlarged active site
pocket.
|
|
|
|
|
|
The above figures are
reprinted
from an Open Access publication published by the ASBMB:
J Biol Chem
(2008,
283,
11355-11363)
copyright 2008.
|
|
|
|
|
|
|
