spacer
spacer

PDBsum entry 2oyu

Go to PDB code: 
protein ligands links
Oxidoreductase PDB id
2oyu
Jmol
Contents
Protein chain
553 a.a. *
Ligands
NAG-NAG ×2
NAG-NAG-BMA
BOG ×2
IMS
HEM
Waters ×52
* Residue conservation analysis
PDB id:
2oyu
Name: Oxidoreductase
Title: Indomethacin-(s)-alpha-ethyl-ethanolamide bound to cyclooxyg
Structure: Prostaglandin g/h synthase 1. Chain: p. Synonym: cyclooxygenase-1, cox-1, prostaglandin-endoperoxid 1, prostaglandin h2 synthase 1, pgh synthase 1, pghs-1, phs ec: 1.14.99.1
Source: Ovis aries. Sheep. Organism_taxid: 9940. Other_details: sheep vesicular gland
Resolution:
2.70Å     R-factor:   0.241     R-free:   0.292
Authors: C.A.Harman,R.M.Garavito
Key ref:
C.A.Harman et al. (2007). Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides. J Biol Chem, 282, 28096-28105. PubMed id: 17656360 DOI: 10.1074/jbc.M701335200
Date:
23-Feb-07     Release date:   24-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P05979  (PGH1_SHEEP) -  Prostaglandin G/H synthase 1
Seq:
Struc:
 
Seq:
Struc:
600 a.a.
553 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.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 = HEM)
matches with 51.16% similarity
+ AH(2)
+ 2 × O(2)
= prostaglandin H(2)
+
+ H(2)O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   6 terms 
  Biochemical function     peroxidase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M701335200 J Biol Chem 282:28096-28105 (2007)
PubMed id: 17656360  
 
 
Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides.
C.A.Harman, M.V.Turman, K.R.Kozak, L.J.Marnett, W.L.Smith, R.M.Garavito.
 
  ABSTRACT  
 
The modification of the nonselective nonsteroidal anti-inflammatory drug, indomethacin, by amidation presents a promising strategy for designing novel cyclooxygenase (COX)-2-selective inhibitors. A series of alpha-substituted indomethacin ethanolamides, which exist as R/S-enantiomeric pairs, provides a means to study the impact of stereochemistry on COX inhibition. Comparative studies revealed that the R- and S-enantiomers of the alpha-substituted analogs inhibit COX-2 with almost equal efficacy, whereas COX-1 is selectively inhibited by the S-enantiomers. Mutagenesis studies have not been able to identify residues that manifest the enantioselectivity in COX-1. In an effort to understand the structural impact of chirality on COX-1 selectivity, the crystal structures of ovine COX-1 in complexes with an enantiomeric pair of these indomethacin ethanolamides were determined at resolutions between 2.75 and 2.85 A. These structures reveal unique, enantiomer-selective interactions within the COX-1 side pocket region that stabilize drug binding and account for the chiral selectivity observed with the (S)-alpha-substituted indomethacin ethanolamides. Kinetic analysis of binding demonstrates that both inhibitors bind quickly utilizing a two-step mechanism. However, the second binding step is readily reversible for the R-enantiomer, whereas for the S-enantiomer, it is not. These studies establish for the first time the structural and kinetic basis of high affinity binding of a neutral inhibitor to COX-1 and demonstrate that the side pocket of COX-1, previously thought to be sterically inaccessible, can serve as a binding pocket for inhibitor association.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. Compound 8 bound in the COX active site of COX-1. A, stereo view of 8 bound in COX active site with simulated annealing omit map difference density (blue) contoured at 3 witha3Å boundary around the ligand. Various residues within the active site are shown with carbons for 8 shown in orange, oxygen red, nitrogen blue, and chlorine purple. B, stereo representation of 8 bound in the COX site in the same manner as the parent compound indomethacin; the chlorobenzoyl group is oriented up toward the top of the channel, the methoxy group on indole ring points toward the side pocket (Leu-517, Phe-518, Ile-523, Gln-192, and Ser-516), and the ethanolamide group with the R-ethyl substitution sits next to Arg-120 and Tyr-355 at the mouth of the active site. Carbon atoms of 8 are shown with same color scheme as in A with the yellow dashed lines representing various interactions (hydrophilic) between ligand and protein residues. The hydroxyl group of the ethanolamide group makes a hydrogen bond with Arg-120 and Glu-524, whereas the (R)-ethyl group is positioned just outside the mouth of the active site. Refinement statistics for both structures are shown in Table 2. All figures presented here were created using the program PyMOL.
Figure 2.
FIGURE 2. Compound 9 bound in the COX active site of COX-1. A, stereo view of 9 fitted into simulated annealing omit map difference density (blue) contoured at 3 witha3Å boundary around the ligand. Carbon atoms of 9 are colored green with heteroatoms colored the same as in 1. B, chlorobenzoyl group of 9 is oriented toward the mouth of the active site; the methoxy group of indole ring is oriented up into the top of the channel, and the ethanolamide group with the (S)-ethyl substitution lies within the side pocket region of the channel. Yellow dashed lines represent various interactions (hydrophobic and hydrophilic) between ligand and protein. The hydroxyl group of the ethanolamide is oriented near the hydrophilic region (cyan) of the side pocket making hydrogen bonds with residues Gln-192 and His-90 whereas the S-ethyl group is oriented into the more hydrophobic region (pink) of the side pocket making van der Waals interactions with Ile-523, Phe-518, and Ile-517. For clarity, an additional polar interaction between Arg-120 and the carbonyl of the chlorobenzoyl moiety is not shown.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 28096-28105) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21365086 E.Parisini, P.Metrangolo, T.Pilati, G.Resnati, and G.Terraneo (2011).
Halogen bonding in halocarbon-protein complexes: a structural survey.
  Chem Soc Rev, 40, 2267-2278.  
19955429 G.Rimon, R.S.Sidhu, D.A.Lauver, J.Y.Lee, N.P.Sharma, C.Yuan, R.A.Frieler, R.C.Trievel, B.R.Lucchesi, and W.L.Smith (2010).
Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.
  Proc Natl Acad Sci U S A, 107, 28-33.
PDB code: 3kk6
20196542 R.S.Deeb, C.Cheung, T.Nuriel, B.D.Lamon, R.K.Upmacis, S.S.Gross, and D.P.Hajjar (2010).
Physical evidence for substrate binding in preventing cyclooxygenase inactivation under nitrative stress.
  J Am Chem Soc, 132, 3914-3922.  
19218248 C.Yuan, R.S.Sidhu, D.V.Kuklev, Y.Kado, M.Wada, I.Song, and W.L.Smith (2009).
Cyclooxygenase Allosterism, Fatty Acid-mediated Cross-talk between Monomers of Cyclooxygenase Homodimers.
  J Biol Chem, 284, 10046-10055.  
19427206 M.J.Walters, A.L.Blobaum, P.J.Kingsley, A.S.Felts, G.A.Sulikowski, and L.J.Marnett (2009).
The influence of double bond geometry in the inhibition of cyclooxygenases by sulindac derivatives.
  Bioorg Med Chem Lett, 19, 3271-3274.  
  20221336 V.F.Roche (2009).
A receptor-grounded approach to teaching nonsteroidal antiinflammatory drug chemistry and structure-activity relationships.
  Am J Pharm Educ, 73, 143.  
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.