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PDBsum entry 1ddx

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1ddx
Jmol
Contents
Protein chains
552 a.a. *
Ligands
NAG-NAG ×4
NAG ×8
BOG ×4
PGX ×4
Waters ×173
* Residue conservation analysis
PDB id:
1ddx
Name: Oxidoreductase
Title: Crystal structure of a mixture of arachidonic acid and prost bound to the cyclooxygenase active site of cox-2: prostagla structure
Structure: Protein (prostaglandin h2 synthase-2). Chain: a, b, c, d. Synonym: cox-2. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Dimer (from PQS)
Resolution:
3.00Å     R-factor:   0.267     R-free:   0.324
Authors: J.R.Kiefer,J.L.Pawlitz,K.T.Moreland,R.A.Stegeman,J.K.Gierse, A.M.Stevens,D.C.Goodwin,S.W.Rowlinson,L.J.Marnett,W.C.Stall R.G.Kurumbail
Key ref:
J.R.Kiefer et al. (2000). Structural insights into the stereochemistry of the cyclooxygenase reaction. Nature, 405, 97. PubMed id: 10811226 DOI: 10.1038/35011103
Date:
11-Nov-99     Release date:   16-May-00    
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.
552 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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
+ AH(2)
+ 2 × O(2)
=
prostaglandin H(2)
Bound ligand (Het Group name = PGX)
corresponds exactly
+
+ 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: 10.1038/35011103 Nature 405:97 (2000)
PubMed id: 10811226  
 
 
Structural insights into the stereochemistry of the cyclooxygenase reaction.
J.R.Kiefer, J.L.Pawlitz, K.T.Moreland, R.A.Stegeman, W.F.Hood, J.K.Gierse, A.M.Stevens, D.C.Goodwin, S.W.Rowlinson, L.J.Marnett, W.C.Stallings, R.G.Kurumbail.
 
  ABSTRACT  
 
Cyclooxygenases are bifunctional enzymes that catalyse the first committed step in the synthesis of prostaglandins, thromboxanes and other eicosanoids. The two known cyclooxygenases isoforms share a high degree of amino-acid sequence similarity, structural topology and an identical catalytic mechanism. Cyclooxygenase enzymes catalyse two sequential reactions in spatially distinct, but mechanistically coupled active sites. The initial cyclooxygenase reaction converts arachidonic acid (which is achiral) to prostaglandin G2 (which has five chiral centres). The subsequent peroxidase reaction reduces prostaglandin G2 to prostaglandin H2. Here we report the co-crystal structures of murine apo-cyclooxygenase-2 in complex with arachidonic acid and prostaglandin. These structures suggest the molecular basis for the stereospecificity of prostaglandin G2 synthesis.
 
  Selected figure(s)  
 
Figure 2.
Figure 2: COX-2 dimer interface solvent channel. The two monomers (coloured green and blue) of the COX-2 dimer are shown from the membrane face (a) or side (b). Cyclooxygenase and peroxidase active sites are marked by AA (red) and haem molecules (orange, superimposed onto the H207A-AA structure), respectively. Solvent molecules are shown as yellow spheres.
Figure 4.
Figure 4: Stereo diagram of the models of AA (a) and PGH[2] ( b) bound at the cyclooxygenase active site. Dashed lines indicate hydrogen bonds or ion pairs formed. The double bonds of the AA and PGH[2] are coloured blue. Protein side chains shown are within van der Waals contact of the ligand. The C13 pro(S)-hydrogen (purple) and pro(R)-hydrogen (gold) of AA are shown for reference.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2000, 405, 97-0) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21421123 A.L.Tsai, G.Wu, C.E.Rogge, J.M.Lü, S.Peng, W.A.van der Donk, G.Palmer, G.J.Gerfen, and R.J.Kulmacz (2011).
Structural comparisons of arachidonic acid-induced radicals formed by prostaglandin H synthase-1 and -2.
  J Inorg Biochem, 105, 366-374.  
21394223 G.Wu, J.M.Lü, W.A.van der Donk, R.J.Kulmacz, and A.L.Tsai (2011).
Cyclooxygenase reaction mechanism of prostaglandin h synthase from deuterium kinetic isotope effects.
  J Inorg Biochem, 105, 382-390.  
20460788 A.K.Tewari, P.Srivastava, V.P.Singh, A.Singh, R.K.Goel, and C.G.Mohan (2010).
Novel anti-inflammatory agents based on pyrazole based dimeric compounds; design, synthesis, docking and in vivo activity.
  Chem Pharm Bull (Tokyo), 58, 634-638.  
19728984 A.L.Tsai, and R.J.Kulmacz (2010).
Prostaglandin H synthase: resolved and unresolved mechanistic issues.
  Arch Biochem Biophys, 493, 103-124.  
20808785 P.Wang, H.W.Bai, and B.T.Zhu (2010).
Structural basis for certain naturally occurring bioflavonoids to function as reducing co-substrates of cyclooxygenase I and II.
  PLoS One, 5, 0.  
20237816 S.Bouaziz-Terrachet, A.Toumi-Maouche, B.Maouche, and S.Taïri-Kellou (2010).
Modeling the binding modes of stilbene analogs to cyclooxygenase-2: a molecular docking study.
  J Mol Model, 16, 1919-1929.  
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.  
20174456 D.S.Cerutti, R.E.Duke, T.A.Darden, and T.P.Lybrand (2009).
Staggered Mesh Ewald: An extension of the Smooth Particle-Mesh Ewald method adding great versatility.
  J Chem Theory Comput, 5, 2322.  
19754086 J.Michel, J.Tirado-Rives, and W.L.Jorgensen (2009).
Prediction of the water content in protein binding sites.
  J Phys Chem B, 113, 13337-13346.  
18942723 S.Wan, and P.V.Coveney (2009).
A comparative study of the COX-1 and COX-2 isozymes bound to lipid membranes.
  J Comput Chem, 30, 1038-1050.  
19289462 U.Garscha, and E.H.Oliw (2009).
Leucine/Valine Residues Direct Oxygenation of Linoleic Acid by (10R)- and (8R)-Dioxygenases: EXPRESSION AND SITE-DIRECTED MUTAGENESIS OF (10R)-DIOXYGENASE WITH EPOXYALCOHOL SYNTHASE ACTIVITY.
  J Biol Chem, 284, 13755-13765.  
  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.  
18427121 J.Qvist, M.Davidovic, D.Hamelberg, and B.Halle (2008).
A dry ligand-binding cavity in a solvated protein.
  Proc Natl Acad Sci U S A, 105, 6296-6301.  
18201917 J.Rand Doyen, N.Yucer, L.M.Lichtenberger, and R.J.Kulmacz (2008).
Phospholipid actions on PGHS-1 and -2 cyclooxygenase kinetics.
  Prostaglandins Other Lipid Mediat, 85, 134-143.  
19090923 M.Khoshneviszadeh, N.Edraki, R.Miri, and B.Hemmateenejad (2008).
Exploring QSAR for substituted 2-sulfonyl-phenyl-indol derivatives as potent and selective COX-2 inhibitors using different chemometrics tools.
  Chem Biol Drug Des, 72, 564-574.  
17984087 R.V.Frolov, I.G.Berim, and S.Singh (2008).
Inhibition of delayed rectifier potassium channels and induction of arrhythmia: a novel effect of celecoxib and the mechanism underlying it.
  J Biol Chem, 283, 1518-1524.  
18038897 A.M.Ali, G.E.Saber, N.M.Mahfouz, M.A.El-Gendy, A.A.Radwan, and M.A.Hamid (2007).
Synthesis and three-dimensional qualitative structure selectivity relationship of 3,5-disubstituted-2,4-thiazolidinedione derivatives as COX2 inhibitors.
  Arch Pharm Res, 30, 1186-1204.  
17301694 C.R.Lee, F.G.Bottone, J.M.Krahn, L.Li, H.W.Mohrenweiser, M.E.Cook, R.M.Petrovich, D.A.Bell, T.E.Eling, and D.C.Zeldin (2007).
Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1).
  Pharmacogenet Genomics, 17, 145-160.  
17409707 S.Muraoka, and T.Miura (2007).
[Metabolism of non-steroidal anti-inflammatory drugs by peroxidase: implication for gastrointestinal mucosal lesions]
  Yakugaku Zasshi, 127, 749-756.  
17204562 T.Young, R.Abel, B.Kim, B.J.Berne, and R.A.Friesner (2007).
Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding.
  Proc Natl Acad Sci U S A, 104, 808-813.  
18031619 Y.C.Chen, and K.T.Chen (2007).
Novel selective inhibitors of hydroxyxanthone derivatives for human cyclooxygenase-2.
  Acta Pharmacol Sin, 28, 2027-2032.  
16606823 C.Yuan, C.J.Rieke, G.Rimon, B.A.Wingerd, and W.L.Smith (2006).
Partnering between monomers of cyclooxygenase-2 homodimers.
  Proc Natl Acad Sci U S A, 103, 6142-6147.  
16519515 K.E.Furse, D.A.Pratt, C.Schneider, A.R.Brash, N.A.Porter, and T.P.Lybrand (2006).
Molecular dynamics simulations of arachidonic acid-derived pentadienyl radical intermediate complexes with COX-1 and COX-2: insights into oxygenation regio- and stereoselectivity.
  Biochemistry, 45, 3206-3218.  
16519514 K.E.Furse, D.A.Pratt, N.A.Porter, and T.P.Lybrand (2006).
Molecular dynamics simulations of arachidonic acid complexes with COX-1 and COX-2: insights into equilibrium behavior.
  Biochemistry, 45, 3189-3205.  
17071117 S.Bingham, P.J.Beswick, D.E.Blum, N.M.Gray, and I.P.Chessell (2006).
The role of the cylooxygenase pathway in nociception and pain.
  Semin Cell Dev Biol, 17, 544-554.  
16059664 H.Park, and S.Lee (2005).
Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors.
  J Comput Aided Mol Des, 19, 17-31.  
17191953 R.G.Huff, E.Bayram, H.Tan, S.T.Knutson, M.H.Knaggs, A.B.Richon, P.Santago, and J.S.Fetrow (2005).
Chemical and structural diversity in cyclooxygenase protein active sites.
  Chem Biodivers, 2, 1533-1552.  
14625295 B.Bambai, C.E.Rogge, B.Stec, and R.J.Kulmacz (2004).
Role of Asn-382 and Thr-383 in activation and inactivation of human prostaglandin H synthase cyclooxygenase catalysis.
  J Biol Chem, 279, 4084-4092.  
15507640 C.A.Rue, M.A.Jarvis, A.J.Knoche, H.L.Meyers, V.R.DeFilippis, S.G.Hansen, M.Wagner, K.Früh, D.G.Anders, S.W.Wong, P.A.Barry, and J.A.Nelson (2004).
A cyclooxygenase-2 homologue encoded by rhesus cytomegalovirus is a determinant for endothelial cell tropism.
  J Virol, 78, 12529-12536.  
14594816 C.Schneider, W.E.Boeglin, and A.R.Brash (2004).
Identification of two cyclooxygenase active site residues, Leucine 384 and Glycine 526, that control carbon ring cyclization in prostaglandin biosynthesis.
  J Biol Chem, 279, 4404-4414.  
12814642 R.J.Kulmacz, W.A.van der Donk, and A.L.Tsai (2003).
Comparison of the properties of prostaglandin H synthase-1 and -2.
  Prog Lipid Res, 42, 377-404.  
12574066 R.M.Garavito, and A.M.Mulichak (2003).
The structure of mammalian cyclooxygenases.
  Annu Rev Biophys Biomol Struct, 32, 183-206.  
12925531 S.W.Rowlinson, J.R.Kiefer, J.J.Prusakiewicz, J.L.Pawlitz, K.R.Kozak, A.S.Kalgutkar, W.C.Stallings, R.G.Kurumbail, and L.J.Marnett (2003).
A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385.
  J Biol Chem, 278, 45763-45769.
PDB code: 1pxx
11677234 C.Schneider, W.E.Boeglin, J.J.Prusakiewicz, S.W.Rowlinson, L.J.Marnett, N.Samel, and A.R.Brash (2002).
Control of prostaglandin stereochemistry at the 15-carbon by cyclooxygenases-1 and -2. A critical role for serine 530 and valine 349.
  J Biol Chem, 277, 478-485.  
11258925 J.F.Nemeth, G.P.Hochgesang, L.J.Marnett, R.M.Caprioli, and G.P.Hochensang (2001).
Characterization of the glycosylation sites in cyclooxygenase-2 using mass spectrometry.
  Biochemistry, 40, 3109-3116.  
11006543 L.J.Marnett (2000).
Cyclooxygenase mechanisms.
  Curr Opin Chem Biol, 4, 545-552.  
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.