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PDBsum entry 2vqw
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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 and functional analysis of the human hdac4 catalytic domain reveals a regulatory structural zinc-Binding domain.
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Authors
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M.J.Bottomley,
P.Lo surdo,
P.Di giovine,
A.Cirillo,
R.Scarpelli,
F.Ferrigno,
P.Jones,
P.Neddermann,
R.De francesco,
C.Steinkühler,
P.Gallinari,
A.Carfí.
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Ref.
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J Biol Chem, 2008,
283,
26694-26704.
[DOI no: ]
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PubMed id
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Abstract
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Histone deacetylases (HDACs) regulate chromatin status and gene expression, and
their inhibition is of significant therapeutic interest. To date, no biological
substrate for class IIa HDACs has been identified, and only low activity on
acetylated lysines has been demonstrated. Here, we describe inhibitor-bound and
inhibitor-free structures of the histone deacetylase-4 catalytic domain
(HDAC4cd) and of an HDAC4cd active site mutant with enhanced enzymatic activity
toward acetylated lysines. The structures presented, coupled with activity data,
provide the molecular basis for the intrinsically low enzymatic activity of
class IIa HDACs toward acetylated lysines and reveal active site features that
may guide the design of class-specific inhibitors. In addition, these structures
reveal a conformationally flexible structural zinc-binding domain conserved in
all class IIa enzymes. Importantly, either the mutation of residues coordinating
the structural zinc ion or the binding of a class IIa selective inhibitor
prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex.
Together, these data suggest a key role of the structural zinc-binding domain in
the regulation of class IIa HDAC functions.
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Figure 4.
FIGURE 4. Interactions of HDAC4cd with inhibitors. A,
interactions of the TFMK (yellow carbons) and HA (green carbons)
with HDAC4; the complex structures have PDB codes 2VQJ and 2VQM,
respectively. Red spheres, water molecules. The surface around
the protein is shown for the TFMK-bound HDAC4cd. B,
superposition of HDAC4cd (cyan) bound to TFMK (sticks and
surface) with HDAC8 (yellow) and homology-modeled HDAC1
(magenta). Residues surrounding the trifluoro group are labeled.
Cyan spheres, C  atoms.
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Figure 5.
FIGURE 5. The active sites of HDAC4 and HDAC8. A, the
active site of HDAC8 (yellow side chains) bound to a hydroxamic
acid inhibitor (light brown) from Protein Data Bank entry 1W22
[PDB]
. B, WT HDAC4cd with bound TFMK (yellow carbons) (Protein Data
Bank code 2VQQ) and superposed HA (green carbons) (Protein Data
Bank code 2VQM). The active site closely resembles HDAC8. C, the
active site of GOF HDAC4cd with HA bound (Protein Data Bank code
2VQV); Tyr^976 adopts the inward, class I-like conformation. D,
the active site of GOF HDAC4cd with TFMK bound (Protein Data
Bank code 2VQO); Tyr^976 adopts an outward conformation.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
26694-26704)
copyright 2008.
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