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PDBsum entry 3mz7

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protein ligands metals links
Hydrolase PDB id
3mz7
Jmol
Contents
Protein chain
356 a.a. *
Ligands
B3N
GOL
Metals
_CO
__K ×2
Waters ×146
* Residue conservation analysis
PDB id:
3mz7
Name: Hydrolase
Title: Crystal structure of d101l co2+ hdac8 complexed with m344
Structure: Histone deacetylase 8. Chain: a. Synonym: hd8. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hdac8. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
1.90Å     R-factor:   0.222     R-free:   0.256
Authors: D.P.Dowling,S.G.Gattis,C.A.Fierke,D.W.Christianson
Key ref: D.P.Dowling et al. (2010). Structures of metal-substituted human histone deacetylase 8 provide mechanistic inferences on biological function . Biochemistry, 49, 5048-5056. PubMed id: 20545365 DOI: 10.1021/bi1005046
Date:
11-May-10     Release date:   23-Jun-10    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9BY41  (HDAC8_HUMAN) -  Histone deacetylase 8
Seq:
Struc:
377 a.a.
356 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.5.1.98  - Histone deacetylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   5 terms 
  Biological process     histone H3 deacetylation   11 terms 
  Biochemical function     hydrolase activity     11 terms  

 

 
DOI no: 10.1021/bi1005046 Biochemistry 49:5048-5056 (2010)
PubMed id: 20545365  
 
 
Structures of metal-substituted human histone deacetylase 8 provide mechanistic inferences on biological function .
D.P.Dowling, S.G.Gattis, C.A.Fierke, D.W.Christianson.
 
  ABSTRACT  
 
The metal-dependent histone deacetylases (HDACs) adopt an alpha/beta protein fold first identified in rat liver arginase. Despite insignificant overall amino acid sequence identity, these enzymes share a strictly conserved metal binding site with divergent metal specificity and stoichiometry. HDAC8, originally thought to be a Zn(2+)-metallohydrolase, exhibits increased activity with Co(2+) and Fe(2+) cofactors based on k(cat)/K(M) (Gantt, S. L., Gattis, S. G., and Fierke, C. A. (2006) Biochemistry 45, 6170-6178). Here, we report the first X-ray crystal structures of metallo-substituted HDAC8, Co(2+)-HDAC8, D101L Co(2+)-HDAC8, D101L Mn(2+)-HDAC8, and D101L Fe(2+)-HDAC8, each complexed with the inhibitor M344. Metal content of protein samples in solution is confirmed by inductively coupled plasma mass spectrometry. For the crystalline enzymes, peaks in Bijvoet difference Fourier maps calculated from X-ray diffraction data collected near the respective elemental absorption edges confirm metal substitution. Additional solution studies confirm incorporation of Cu(2+); Fe(3+) and Ni(2+) do not bind under conditions tested. The metal dependence of the substrate K(M) values and the K(i) values of hydroxamate inhibitors that chelate the active site metal are consistent with substrate-metal coordination in the precatalytic Michaelis complex that enhances catalysis. Additionally, although HDAC8 binds Zn(2+) nearly 10(6)-fold more tightly than Fe(2+), the affinities for both metal ions are comparable to the readily exchangeable metal concentrations estimated in living cells, suggesting that HDAC8 could bind either or both Fe(2+) or Zn(2+) in vivo.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21496451 D.M.Griffith, B.Szőcs, T.Keogh, K.Y.Suponitsky, E.Farkas, P.Buglyó, and C.J.Marmion (2011).
Suberoylanilide hydroxamic acid, a potent histone deacetylase inhibitor; its X-ray crystal structure and solid state and solution studies of its Zn(II), Ni(II), Cu(II) and Fe(III) complexes.
  J Inorg Biochem, 105, 763-769.  
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