PDBsum entry 2vqw

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Hydrolase PDB id
Protein chain
382 a.a. *
_ZN ×2
__K ×2
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structure of inhibitor-free hdac4 catalytic domain (with gain-of-function mutation his332tyr)
Structure: Histone deacetylase 4. Chain: g. Fragment: catalytic domain, residues 648-1057. Synonym: hd4. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Heidelberg)
3.00Å     R-factor:   0.234     R-free:   0.261
Authors: 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
Key ref:
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: 18614528 DOI: 10.1074/jbc.M803514200
19-Mar-08     Release date:   05-Aug-08    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P56524  (HDAC4_HUMAN) -  Histone deacetylase 4
1084 a.a.
382 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Histone deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]


DOI no: 10.1074/jbc.M803514200 J Biol Chem 283:26694-26704 (2008)
PubMed id: 18614528  
Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.
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.
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.
  Selected figure(s)  
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.
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.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 26694-26704) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20588319 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.
  J Cereb Blood Flow Metab, 31, 339-350.  
  21374822 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.
  ChemMedChem, 6, 698-712.  
20139990 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.
  Nat Chem Biol, 6, 238-243.  
20122187 M.Comin, and D.Verzotto (2010).
Classification of protein sequences by means of irredundant patterns.
  BMC Bioinformatics, 11, S16.  
20029090 S.L.Gantt, C.G.Joseph, and C.A.Fierke (2010).
Activation and inhibition of histone deacetylase 8 by monovalent cations.
  J Biol Chem, 285, 6036-6043.  
20209563 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.
  ChemMedChem, 5, 598-607.  
19705846 C.A.Olsen, and M.R.Ghadiri (2009).
Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides.
  J Med Chem, 52, 7836-7846.  
19763297 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.
  Org Biomol Chem, 7, 3947-3957.  
19355989 D.Wang (2009).
Computational studies on the histone deacetylases and the design of selective histone deacetylase inhibitors.
  Curr Top Med Chem, 9, 241-256.  
19672313 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.
  PLoS One, 4, e6612.  
19855427 L.Wang, Zoeten, M.I.Greene, and W.W.Hancock (2009).
Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells.
  Nat Rev Drug Discov, 8, 969-981.  
19065135 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.
  Nat Rev Genet, 10, 32-42.  
19424677 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.
  J Mol Med, 87, 785-791.  
19053282 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.
  Biochemistry, 47, 13554-13563.
PDB codes: 3ew8 3ewf 3ezp 3ezt 3f06 3f07 3f0r
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.