spacer
spacer

PDBsum entry 3c0z
Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
3c0z

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chains
383 a.a. *
359 a.a. *
Ligands
SHH ×3
Metals
_ZN ×6
__K ×6
Waters ×332
* Residue conservation analysis
PDB id:
3c0z
Name: Hydrolase
Title: Crystal structure of catalytic domain of human histone deacetylase hdac7 in complex with saha
Structure: Histone deacetylase 7a. Chain: a, b, c. Fragment: catalytic domain: residues 482-903. Synonym: hd7a, hdac7. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hdac7a, hdac7. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.10Å     R-factor:   0.199     R-free:   0.243
Authors: J.Min,A.Schuetz,P.Loppnau,J.Weigelt,M.Sundstrom,C.H.Arrowsmith, A.M.Edwards,A.Bochkarev,A.N.Plotnikov,Structural Genomics Consortium (Sgc)
Key ref:
A.Schuetz et al. (2008). Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. J Biol Chem, 283, 11355-11363. PubMed id: 18285338 DOI: 10.1074/jbc.M707362200
Date:
21-Jan-08     Release date:   19-Feb-08    
Supersedes: 2pqo
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q8WUI4  (HDAC7_HUMAN) -  Histone deacetylase 7 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		952 a.a.
383 a.a.
Protein chain
Pfam   ArchSchema ?
Q8WUI4  (HDAC7_HUMAN) -  Histone deacetylase 7 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		952 a.a.
359 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C: E.C.3.5.1.98  - histone deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: N6-acetyl-L-lysyl-[histone] + H2O = L-lysyl-[histone] + acetate
N(6)-acetyl-L-lysyl-[histone]
 + H2O
 = L-lysyl-[histone]
 + acetate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Key reference    
 
 
DOI no: 10.1074/jbc.M707362200 J Biol Chem 283:11355-11363 (2008)
PubMed id: 18285338  
 
 
Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity.
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.
 
  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.
 
  Selected figure(s)  
 
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.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22498752 C.H.Arrowsmith, C.Bountra, P.V.Fish, K.Lee, and M.Schapira (2012).
Epigenetic protein families: a new frontier for drug discovery.
  Nat Rev Drug Discov, 11, 384-400.  
21188173 A.Linares, F.Dalenc, P.Balaguer, N.Boulle, and V.Cavailles (2011).
Manipulating protein acetylation in breast cancer: a promising approach in combination with hormonal therapies?
  J Biomed Biotechnol, 2011, 856985.  
20437082 A.Krivoruchko, and K.B.Storey (2010).
Epigenetics in anoxia tolerance: a role for histone deacetylases.
  Mol Cell Biochem, 342, 151-161.  
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.  
20142042 K.T.Smith, S.A.Martin-Brown, L.Florens, M.P.Washburn, and J.L.Workman (2010).
Deacetylase inhibitors dissociate the histone-targeting ING2 subunit from the Sin3 complex.
  Chem Biol, 17, 65-74.  
20122187 M.Comin, and D.Verzotto (2010).
Classification of protein sequences by means of irredundant patterns.
  BMC Bioinformatics, 11, S16.  
19784544 R.Higashiyama, S.Miyaki, S.Yamashita, T.Yoshitaka, G.Lindman, Y.Ito, T.Sasho, K.Takahashi, M.Lotz, and H.Asahara (2010).
Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis.
  Mod Rheumatol, 20, 11-17.  
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.  
19917725 S.Malik, S.Jiang, J.P.Garee, E.Verdin, A.V.Lee, B.W.O'Malley, M.Zhang, N.S.Belaguli, and S.Oesterreich (2010).
Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM.
  Mol Cell Biol, 30, 399-412.  
21106123 U.S.Tambunan, and E.K.Wulandari (2010).
Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis.
  BMC Bioinformatics, 11, S16.  
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.  
19349466 A.Bougdour, D.Maubon, P.Baldacci, P.Ortet, O.Bastien, A.Bouillon, J.C.Barale, H.Pelloux, R.Ménard, and M.A.Hakimi (2009).
Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites.
  J Exp Med, 206, 953-966.  
19093884 A.K.Oyelere, P.C.Chen, W.Guerrant, S.C.Mwakwari, R.Hood, Y.Zhang, and Y.Fan (2009).
Non-peptide macrocyclic histone deacetylase inhibitors.
  J Med Chem, 52, 456-468.  
19239270 A.Montero, J.M.Beierle, C.A.Olsen, and M.R.Ghadiri (2009).
Design, synthesis, biological evaluation, and structural characterization of potent histone deacetylase inhibitors based on cyclic alpha/beta-tetrapeptide architectures.
  J Am Chem Soc, 131, 3033-3041.  
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.  
19484127 C.L.Benn, R.Butler, L.Mariner, J.Nixon, H.Moffitt, M.Mielcarek, B.Woodman, and G.P.Bates (2009).
Genetic knock-down of HDAC7 does not ameliorate disease pathogenesis in the R6/2 mouse model of Huntington's disease.
  PLoS One, 4, e5747.  
19885462 D.Griffith, M.P.Morgan, and C.J.Marmion (2009).
A novel anti-cancer bifunctional platinum drug candidate with dual DNA binding and histone deacetylase inhibitory activity.
  Chem Commun (Camb), (), 6735-6737.  
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.  
18845268 K.T.Smith, and J.L.Workman (2009).
Histone deacetylase inhibitors: anticancer compounds.
  Int J Biochem Cell Biol, 41, 21-25.  
19855427 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.
  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.  
18725319 R.Codd, N.Braich, J.Liu, C.Z.Soe, and A.A.Pakchung (2009).
Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A.
  Int J Biochem Cell Biol, 41, 736-739.  
19090524 S.Schäfer, L.Saunders, S.Schlimme, V.Valkov, J.M.Wagner, F.Kratz, W.Sippl, E.Verdin, and M.Jung (2009).
Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors.
  ChemMedChem, 4, 283-290.  
19721249 T.Suzuki (2009).
Explorative study on isoform-selective histone deacetylase inhibitors.
  Chem Pharm Bull (Tokyo), 57, 897-906.  
18625722 C.Gao, C.C.Ho, E.Reineke, M.Lam, X.Cheng, K.J.Stanya, Y.Liu, S.Chakraborty, H.M.Shih, and H.Y.Kao (2008).
Histone deacetylase 7 promotes PML sumoylation and is essential for PML nuclear body formation.
  Mol Cell Biol, 28, 5658-5667.  
18425769 D.R.Walkinshaw, S.Tahmasebi, N.R.Bertos, and X.J.Yang (2008).
Histone deacetylases as transducers and targets of nuclear signaling.
  J Cell Biochem, 104, 1541-1552.  
  19008999 D.R.Walkinshaw, and X.J.Yang (2008).
Histone deacetylase inhibitors as novel anticancer therapeutics.
  Curr Oncol, 15, 237-243.  
18800048 P.A.Cole (2008).
Chemical probes for histone-modifying enzymes.
  Nat Chem Biol, 4, 590-597.  
18626575 Z.Zhou, X.Song, B.Li, and M.I.Greene (2008).
FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity.
  Immunol Res, 42, 19-28.  
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.

 

spacer
spacer