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PDBsum entry 3f07
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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
3f07

 

 

 

 

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Contents
Protein chains
366 a.a. *
340 a.a. *
Ligands
AGE ×2
Metals
__K ×6
_ZN ×4
Waters ×14
* Residue conservation analysis
PDB id:
3f07
Name: Hydrolase
Title: Crystal structure analysis of human hdac8 complexed with apha in a new monoclinic crystal form
Structure: Histone deacetylase 8. Chain: a, b, c. Synonym: hd8. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cda07, hdac8, hdacl1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
3.30Å     R-factor:   0.216     R-free:   0.260
Authors: D.P.Dowling,S.L.Gantt,S.G.Gattis,C.A.Fierke,D.W.Christianson
Key ref: D.P.Dowling et al. (2008). Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors. Biochemistry, 47, 13554-13563. PubMed id: 19053282
Date:
24-Oct-08     Release date:   30-Dec-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q9BY41  (HDAC8_HUMAN) -  Histone deacetylase 8 from Homo sapiens
Seq:
Struc: 		377 a.a.
366 a.a.
Protein chain
Pfam   ArchSchema ?
Q9BY41  (HDAC8_HUMAN) -  Histone deacetylase 8 from Homo sapiens
Seq:
Struc: 		377 a.a.
340 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    
 
 
Biochemistry 47:13554-13563 (2008)
PubMed id: 19053282  
 
 
Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.
D.P.Dowling, S.L.Gantt, S.G.Gattis, C.A.Fierke, D.W.Christianson.
 
  ABSTRACT  
 
Metal-dependent histone deacetylases (HDACs) require Zn(2+) or Fe(2+) to regulate the acetylation of lysine residues in histones and other proteins in eukaryotic cells. Isozyme HDAC8 is perhaps the archetypical member of the class I HDAC family and serves as a paradigm for studying structure-function relationships. Here, we report the structures of HDAC8 complexes with trichostatin A and 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA) in a new crystal form. The structure of the APHA complex reveals that the hydroxamate CO group accepts a hydrogen bond from Y306 but does not coordinate to Zn(2+) with favorable geometry, perhaps due to the constraints of its extended pi system. Additionally, since APHA binds to only two of the three protein molecules in the asymmetric unit of this complex, the structure of the third monomer represents the first structure of HDAC8 in the unliganded state. Comparison of unliganded and liganded structures illustrates ligand-induced conformational changes in the L2 loop that likely accompany substrate binding and catalysis. Furthermore, these structures, along with those of the D101N, D101E, D101A, and D101L variants, support the proposal that D101 is critical for the function of the L2 loop. However, amino acid substitutions for D101 can also trigger conformational changes of Y111 and W141 that perturb the substrate binding site. Finally, the structure of H143A HDAC8 complexed with an intact acetylated tetrapeptide substrate molecule confirms the importance of D101 for substrate binding and reveals how Y306 and the active site zinc ion together bind and activate the scissile amide linkage of acetyllysine.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22885700 M.A.Deardorff, M.Bando, R.Nakato, E.Watrin, T.Itoh, M.Minamino, K.Saitoh, M.Komata, Y.Katou, D.Clark, K.E.Cole, E.De Baere, C.Decroos, N.Di Donato, S.Ernst, L.J.Francey, Y.Gyftodimou, K.Hirashima, M.Hullings, Y.Ishikawa, C.Jaulin, M.Kaur, T.Kiyono, P.M.Lombardi, L.Magnaghi-Jaulin, G.R.Mortier, N.Nozaki, M.B.Petersen, H.Seimiya, V.M.Siu, Y.Suzuki, K.Takagaki, J.J.Wilde, P.J.Willems, C.Prigent, G.Gillessen-Kaesbach, D.W.Christianson, F.J.Kaiser, L.G.Jackson, T.Hirota, I.D.Krantz, and K.Shirahige (2012).
HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.
  Nature, 489, 313-317.  
22230954 P.J.Watson, L.Fairall, G.M.Santos, and J.W.Schwabe (2012).
Structure of HDAC3 bound to co-repressor and inositol tetraphosphate.
  Nature, 481, 335-340.
PDB code: 4a69
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.  
19886628 B.He, S.Velaparthi, G.Pieffet, C.Pennington, A.Mahesh, D.L.Holzle, M.Brunsteiner, R.van Breemen, S.Y.Blond, and P.A.Petukhov (2009).
Binding ensemble profiling with photoaffinity labeling (BEProFL) approach: mapping the binding poses of HDAC8 inhibitors.
  J Med Chem, 52, 7003-7013.  
19534534 R.A.Casero, and P.M.Woster (2009).
Recent advances in the development of polyamine analogues as antitumor agents.
  J Med Chem, 52, 4551-4573.  
20161624 R.Wu, P.Hu, S.Wang, Z.Cao, and Y.Zhang (2009).
Flexibility of Catalytic Zinc Coordination in Thermolysin and HDAC8: A Born-Oppenheimer ab initio QM/MM Molecular Dynamics Study.
  J Chem Theory Comput, 6, 337.  
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 code is shown on the right.

 

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