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PDBsum entry 3hs6

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
3hs6
Jmol
Contents
Protein chains
551 a.a. *
Ligands
EPA ×2
AKR ×4
COH ×2
NAG-NAG ×2
NAG-NAG-MAN
NAG ×2
BOG ×2
EDO ×8
NAG-NDG
Waters ×487
* Residue conservation analysis
PDB id:
3hs6
Name: Oxidoreductase
Title: X-ray crystal structure of eicosapentaenoic acid bound to th cyclooxygenase channel of cyclooxygenase-2
Structure: Prostaglandin g/h synthase 2. Chain: a, b. Synonym: cyclooxygenase-2, cox-2, prostaglandin-endoperoxid 2, prostaglandin h2 synthase 2, pgh synthase 2, pghs-2, phs glucocorticoid-regulated inflammatory cyclooxygenase, gripg protein, macrophage activation-associated marker protein p7 2. Engineered: yes. Mutation: yes
Source: Mus musculus. Mouse. Organism_taxid: 10090. Gene: ptgs2, cox-2, cox2, pghs-b, tis10. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.40Å     R-factor:   0.179     R-free:   0.223
Authors: A.J.Vecchio,D.M.Simmons,M.G.Malkowski
Key ref: A.J.Vecchio et al. (2010). Structural basis of fatty acid substrate binding to cyclooxygenase-2. J Biol Chem, 285, 22152-22163. PubMed id: 20463020 DOI: 10.1074/jbc.M110.119867
Date:
10-Jun-09     Release date:   12-May-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q05769  (PGH2_MOUSE) -  Prostaglandin G/H synthase 2
Seq:
Struc:
 
Seq:
Struc:
604 a.a.
551 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.1.14.99.1  - Prostaglandin-endoperoxide synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Arachidonate + AH2 + 2 O2 = prostaglandin H2 + A + H2O
Arachidonate
Bound ligand (Het Group name = EPA)
corresponds exactly
+ AH(2)
+ 2 × O(2)
=
prostaglandin H(2)
Bound ligand (Het Group name = COH)
matches with 51.00% similarity
+
+ H(2)O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     protein complex   8 terms 
  Biological process     maintenance of blood-brain barrier   64 terms 
  Biochemical function     lipid binding     10 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M110.119867 J Biol Chem 285:22152-22163 (2010)
PubMed id: 20463020  
 
 
Structural basis of fatty acid substrate binding to cyclooxygenase-2.
A.J.Vecchio, D.M.Simmons, M.G.Malkowski.
 
  ABSTRACT  
 
The cyclooxygenases (COX-1 and COX-2) are membrane-associated, heme-containing homodimers that generate PGH2 from arachidonic acid (AA). While AA is the preferred substrate, other fatty acids are oxygenated by these enzymes with varying efficiencies. We determined the crystal structures of AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) bound to Co(3+)-protoporphyrin IX reconstituted murine COX-2 to 2.1A, 2.4A, and 2.65A, respectively. AA, EPA, and DHA bind in different conformations in each monomer constituting the homodimer in their respective structures such that one monomer exhibits non-productive binding and the other productive binding of the substrate in the cyclooxygenase channel. The interactions identified between protein and substrate when bound to COX-1 are conserved in our COX-2 structures, with the only notable difference being the lack of interaction of the carboxylate of AA and EPA with the side chain of Arg-120. Leu-531 exhibits a different side chain conformation when the non-productive and productive binding modes of AA are compared. Unlike COX-1, mutating this residue to Ala, Phe, Pro, or Thr did not result in a significant loss of activity or substrate binding affinity. Determination of the L531F:AA crystal structure resulted in AA binding in the same global conformation in each monomer. We speculate that the mobility of the Leu-531 side chain increases the volume available at the opening of the cyclooxygenase channel and contributes to the observed ability of COX-2 to oxygenate a broad spectrum of fatty acid and fatty ester substrates.