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PDBsum entry 2vqj
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Structure of hdac4 catalytic domain bound to a trifluoromethylketone inhbitor
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Structure:
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Histone deacetylase 4. Chain: a. Fragment: catalytic domain, residues 648-1057. Synonym: hd4. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.10Å
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R-factor:
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0.228
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R-free:
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0.276
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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.Steinkuhler, P.Gallinari,A.Carfi
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Key ref:
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M.J.Bottomley
et al.
(2008).
Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.
J Biol Chem,
283,
26694-26704.
PubMed id:
DOI:
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Date:
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17-Mar-08
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Release date:
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08-Jul-08
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PROCHECK
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Headers
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References
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P56524
(HDAC4_HUMAN) -
Histone deacetylase 4 from Homo sapiens
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Seq:
Struc:
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1084 a.a.
402 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.5.1.98
- histone deacetylase.
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Reaction:
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N6-acetyl-L-lysyl-[histone] + H2O = L-lysyl-[histone] + acetate
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N(6)-acetyl-L-lysyl-[histone]
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+
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H2O
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=
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L-lysyl-[histone]
Bound ligand (Het Group name = )
matches with 42.86% similarity
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+
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acetate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Biol Chem
283:26694-26704
(2008)
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PubMed id:
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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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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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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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Selected figure(s)
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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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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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J.Cheng,
M.Uchida,
W.Zhang,
M.R.Grafe,
P.S.Herson,
and
P.D.Hurn
(2011).
Role of salt-induced kinase 1 in androgen neuroprotection against cerebral ischemia.
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J Cereb Blood Flow Metab,
31,
339-350.
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S.Valente,
M.Tardugno,
M.Conte,
R.Cirilli,
A.Perrone,
R.Ragno,
S.Simeoni,
A.Tramontano,
S.Massa,
A.Nebbioso,
M.Miceli,
G.Franci,
G.Brosch,
L.Altucci,
and
A.Mai
(2011).
Novel cinnamyl hydroxyamides and 2-aminoanilides as histone deacetylase inhibitors: apoptotic induction and cytodifferentiation activity.
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ChemMedChem,
6,
698-712.
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J.E.Bradner,
N.West,
M.L.Grachan,
E.F.Greenberg,
S.J.Haggarty,
T.Warnow,
and
R.Mazitschek
(2010).
Chemical phylogenetics of histone deacetylases.
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Nat Chem Biol,
6,
238-243.
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M.Comin,
and
D.Verzotto
(2010).
Classification of protein sequences by means of irredundant patterns.
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BMC Bioinformatics,
11,
S16.
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S.L.Gantt,
C.G.Joseph,
and
C.A.Fierke
(2010).
Activation and inhibition of histone deacetylase 8 by monovalent cations.
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J Biol Chem,
285,
6036-6043.
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W.J.Huang,
C.C.Chen,
S.W.Chao,
S.S.Lee,
F.L.Hsu,
Y.L.Lu,
M.F.Hung,
and
C.I.Chang
(2010).
Synthesis of N-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase.
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ChemMedChem,
5,
598-607.
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C.A.Olsen,
and
M.R.Ghadiri
(2009).
Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides.
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J Med Chem,
52,
7836-7846.
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C.Fäh,
L.A.Hardegger,
L.Baitsch,
W.B.Schweizer,
S.Meyer,
D.Bur,
and
F.Diederich
(2009).
New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic alpha,alpha-difluoroketone hydrates.
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Org Biomol Chem,
7,
3947-3957.
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D.Wang
(2009).
Computational studies on the histone deacetylases and the design of selective histone deacetylase inhibitors.
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Curr Top Med Chem,
9,
241-256.
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I.Rajan,
K.V.Savelieva,
G.L.Ye,
C.Y.Wang,
M.M.Malbari,
C.Friddle,
T.H.Lanthorn,
and
W.Zhang
(2009).
Loss of the putative catalytic domain of HDAC4 leads to reduced thermal nociception and seizures while allowing normal none development.
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PLoS One,
4,
e6612.
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L.Wang,
E.F.de Zoeten,
M.I.Greene,
and
W.W.Hancock
(2009).
Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells.
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Nat Rev Drug Discov,
8,
969-981.
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M.Haberland,
R.L.Montgomery,
and
E.N.Olson
(2009).
The many roles of histone deacetylases in development and physiology: implications for disease and therapy.
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Nat Rev Genet,
10,
32-42.
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S.Oka,
T.Ago,
T.Kitazono,
D.Zablocki,
and
J.Sadoshima
(2009).
The role of redox modulation of class II histone deacetylases in mediating pathological cardiac hypertrophy.
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J Mol Med,
87,
785-791.
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D.P.Dowling,
S.L.Gantt,
S.G.Gattis,
C.A.Fierke,
and
D.W.Christianson
(2008).
Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.
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Biochemistry,
47,
13554-13563.
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PDB codes:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
