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PDBsum entry 1diy

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Oxidoreductase PDB id
1diy
Jmol PyMol
Contents
Protein chain
553 a.a. *
Ligands
NAG-NDG
NAG-NAG-BMA-BMA-
MAN
NAG-NAG
BOG ×4
COH
ACD
Waters ×109
* Residue conservation analysis
PDB id:
1diy
Name: Oxidoreductase
Title: Crystal structure of arachidonic acid bound in the cyclooxyg active site of pghs-1
Structure: Prostaglandin h2 synthase-1. Chain: a. Ec: 1.14.99.1
Source: Ovis aries. Sheep. Organism_taxid: 9940. Organ: seminal vessicle
Biol. unit: Dimer (from PDB file)
Resolution:
3.00Å     R-factor:   0.215     R-free:   0.290
Authors: M.G.Malkowski,S.L.Ginell,W.L.Smith,R.M.Garavito
Key ref:
M.G.Malkowski et al. (2000). The productive conformation of arachidonic acid bound to prostaglandin synthase. Science, 289, 1933-1937. PubMed id: 10988074 DOI: 10.1126/science.289.5486.1933
Date:
30-Nov-99     Release date:   22-Sep-00    
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 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 = COH)
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!
  Cellular component     membrane   8 terms 
  Biological process     oxidation-reduction process   11 terms 
  Biochemical function     drug binding     8 terms  

 

 
    reference    
 
 
DOI no: 10.1126/science.289.5486.1933 Science 289:1933-1937 (2000)
PubMed id: 10988074  
 
 
The productive conformation of arachidonic acid bound to prostaglandin synthase.
M.G.Malkowski, S.L.Ginell, W.L.Smith, R.M.Garavito.
 
  ABSTRACT  
 
Prostaglandin H synthase-1 and -2 (PGHS-1 and -2) catalyze the committed step in prostaglandin synthesis and are targets for nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin. We have determined the structure of PGHS-1 at 3 angstrom resolution with arachidonic acid (AA) bound in a chemically productive conformation. The fatty acid adopts an extended L-shaped conformation that positions the 13proS hydrogen of AA for abstraction by tyrosine-385, the likely radical donor. A space also exists for oxygen addition on the antarafacial surface of the carbon in the 11-position (C-11). While this conformation allows endoperoxide formation between C-11 and C-9, it also implies that a subsequent conformational rearrangement must occur to allow formation of the C-8/C-12 bond and to position C-15 for attack by a second molecule of oxygen.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. A schematic of interactions between AA and COX channel residues (30). Carbon atoms of AA are yellow, oxygen atoms red, and the 13proS hydrogen blue. All dashed lines represent interactions within 4.0 Å between the specific side chain atom of the protein and AA; the structures AA-1 and AA-2 revealed the same set of 49 contacts. Only two of these contacts between AA and the COX channel residues are hydrophilic. The carboxylate forms a salt bridge to the guanidinium atom of Arg120 (distance = 2.4 Å; angle = 143°) and a hydrogen bond to the OH group of Tyr355 (distance = 3.1 Å; angle = 115°). (Inset) A schematic of the chemical structure of AA.
Figure 4.
Fig. 4. Mechanistic sequence for converting AA to PGG[2] (30). Abstraction of the 13-proS hydrogen by the tyrosyl radical leads to the migration of the radical to C-11 on AA. Attack of molecular oxygen, coming from the base of the COX channel, occurs on the side antarafacial to hydrogen abstraction. As the 11R-peroxyl radical swings over C-8 for an R-side attack on C-9 to form the endoperoxide bridge, C-12 is brought closer to C-8 via rotation about the C-10/C-11 bond allowing the formation of the cyclopentane ring. The movement of C-12 also positions C-15 optimally for addition of a second molecule of oxygen, formation of PGG[2], and the migration of the radical back to Tyr385.
 
  The above figures are reprinted by permission from the AAAs: Science (2000, 289, 1933-1937) 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.  
21360823 C.Cena, P.Tosco, E.Marini, L.Lazzarato, M.Piccinini, C.Ramondetti, E.Lupino, R.Fruttero, and A.Gasco (2011).
Nitrooxyacyl Derivatives of Salicylic Acid: Aspirin-Like Molecules that Covalently Inactivate Cyclooxygenase-1.
  ChemMedChem, 6, 523-530.  
21403766 J.M.Lü, C.E.Rogge, G.Wu, R.J.Kulmacz, W.A.van der Donk, and A.L.Tsai (2011).
Cyclooxygenase reaction mechanism of PGHS--evidence for a reversible transition between a pentadienyl radical and a new tyrosyl radical by nitric oxide trapping.
  J Inorg Biochem, 105, 356-365.  
21310230 Y.Xiao, Y.Gu, P.Purwaha, K.Ni, B.Law, S.Mallik, and S.Y.Qian (2011).
Characterization of free radicals formed from COX-catalyzed DGLA peroxidation.
  Free Radic Biol Med, 50, 1163-1170.  
19728984 A.L.Tsai, and R.J.Kulmacz (2010).
Prostaglandin H synthase: resolved and unresolved mechanistic issues.
  Arch Biochem Biophys, 493, 103-124.  
20450491 B.Calamini, K.Ratia, M.G.Malkowski, M.Cuendet, J.M.Pezzuto, B.D.Santarsiero, and A.D.Mesecar (2010).
Pleiotropic mechanisms facilitated by resveratrol and its metabolites.
  Biochem J, 429, 273-282.  
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
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.  
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.  
19928795 M.V.Turman, P.J.Kingsley, and L.J.Marnett (2009).
Characterization of an AM404 analogue, N-(3-hydroxyphenyl)arachidonoylamide, as a substrate and inactivator of prostaglandin endoperoxide synthase.
  Biochemistry, 48, 12233-12241.  
19105592 O.Wangpradit, S.V.Mariappan, L.M.Teesch, M.W.Duffel, K.Norstrom, L.W.Robertson, and G.Luthe (2009).
Oxidation of 4-chlorobiphenyl metabolites to electrophilic species by prostaglandin H synthase.
  Chem Res Toxicol, 22, 64-71.  
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.  
20476924 A.Calin (2008).
Celecoxib and ankylosing spondylitis.
  Expert Rev Clin Immunol, 4, 339-349.  
18304833 J.M.Lee, J.Yanagawa, K.A.Peebles, S.Sharma, J.T.Mao, and S.M.Dubinett (2008).
Inflammation in lung carcinogenesis: new targets for lung cancer chemoprevention and treatment.
  Crit Rev Oncol Hematol, 66, 208-217.  
18596034 M.Koszelak-Rosenblum, A.C.Krol, D.M.Simmons, C.C.Goulah, L.Wroblewski, and M.G.Malkowski (2008).
His-311 and Arg-559 are key residues involved in fatty acid oxygenation in pathogen-inducible oxygenase.
  J Biol Chem, 283, 24962-24971.  
18247411 M.Zamocky, C.Jakopitsch, P.G.Furtmüller, C.Dunand, and C.Obinger (2008).
The peroxidase-cyclooxygenase superfamily: Reconstructed evolution of critical enzymes of the innate immune system.
  Proteins, 72, 589-605.  
  18949072 O.Sperandio, M.A.Miteva, K.Segers, G.A.Nicolaes, and B.O.Villoutreix (2008).
Screening Outside the Catalytic Site: Inhibition of Macromolecular Inter-actions Through Structure-Based Virtual Ligand Screening Experiments.
  Open Biochem J, 2, 29-37.  
  19209280 P.Patrignani, S.Tacconelli, and M.L.Capone (2008).
Risk management profile of etoricoxib: an example of personalized medicine.
  Ther Clin Risk Manag, 4, 983-997.  
18227065 R.P.McAndrew, Y.Wang, A.W.Mohsen, M.He, J.Vockley, and J.J.Kim (2008).
Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase.
  J Biol Chem, 283, 9435-9443.
PDB code: 3b96
18346461 S.R.Shaikh, and M.Edidin (2008).
Polyunsaturated fatty acids and membrane organization: elucidating mechanisms to balance immunotherapy and susceptibility to infection.
  Chem Phys Lipids, 153, 24-33.  
17524979 C.Schneider, D.A.Pratt, N.A.Porter, and A.R.Brash (2007).
Control of oxygenation in lipoxygenase and cyclooxygenase catalysis.
  Chem Biol, 14, 473-488.  
17944566 K.A.Peebles, J.M.Lee, J.T.Mao, S.Hazra, K.L.Reckamp, K.Krysan, M.Dohadwala, E.L.Heinrich, T.C.Walser, X.Cui, F.E.Baratelli, E.Garon, S.Sharma, and S.M.Dubinett (2007).
Inflammation and lung carcinogenesis: applying findings in prevention and treatment.
  Expert Rev Anticancer Ther, 7, 1405-1421.  
17646652 K.Segers, O.Sperandio, M.Sack, R.Fischer, M.A.Miteva, J.Rosing, G.A.Nicolaes, and B.O.Villoutreix (2007).
Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V.
  Proc Natl Acad Sci U S A, 104, 12697-12702.  
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.  
16401081 C.E.Rogge, B.Ho, W.Liu, R.J.Kulmacz, and A.L.Tsai (2006).
Role of Tyr348 in Tyr385 radical dynamics and cyclooxygenase inhibitor interactions in prostaglandin H synthase-2.
  Biochemistry, 45, 523-532.  
16371762 C.Hanjis, W.H.Frishman, and R.G.Lerner (2006).
Aspirin resistance: mechanisms and clinical implications.
  Cardiol Rev, 14, 18-25.  
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.  
20477620 L.Zhao, T.Grosser, S.Fries, L.Kadakia, H.Wang, J.Zhao, and R.Falotico (2006).
Lipoxygenase and prostaglandin G/H synthase cascades in cardiovascular disease.
  Expert Rev Clin Immunol, 2, 649-658.  
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.  
  16582486 T.Lloyd, A.Krol, D.Campanaro, and M.Malkowski (2006).
Purification, crystallization and preliminary X-ray diffraction analysis of pathogen-inducible oxygenase (PIOX) from Oryza sativa.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 365-367.  
16732282 Y.Yu, J.Fan, X.S.Chen, D.Wang, A.J.Klein-Szanto, R.L.Campbell, G.A.FitzGerald, and C.D.Funk (2006).
Genetic model of selective COX2 inhibition reveals novel heterodimer signaling.
  Nat Med, 12, 699-704.  
16149114 C.Drahl, B.F.Cravatt, and E.J.Sorensen (2005).
Protein-reactive natural products.
  Angew Chem Int Ed Engl, 44, 5788-5809.  
15626708 C.J.daCosta, D.E.Kaiser, and J.E.Baenziger (2005).
Role of glycosylation and membrane environment in nicotinic acetylcholine receptor stability.
  Biophys J, 88, 1755-1764.  
16157595 G.Coffa, A.N.Imber, B.C.Maguire, G.Laxmikanthan, C.Schneider, B.J.Gaffney, and A.R.Brash (2005).
On the relationships of substrate orientation, hydrogen abstraction, and product stereochemistry in single and double dioxygenations by soybean lipoxygenase-1 and its Ala542Gly mutant.
  J Biol Chem, 280, 38756-38766.  
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.  
15700978 J.C.Wilson, G.Wu, A.L.Tsai, and G.J.Gerfen (2005).
Determination of the structural environment of the tyrosyl radical in prostaglandin H2 synthase-1: a high frequency ENDOR/EPR study.
  J Am Chem Soc, 127, 1618-1619.  
15670154 M.Hamberg (2005).
Hidden stereospecificity in the biosynthesis of divinyl ether fatty acids.
  FEBS J, 272, 736-743.  
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.  
15897974 S.Neeraja, B.Ramakrishna, A.S.Sreenath, G.V.Reddy, P.R.Reddy, and P.Reddanna (2005).
Novel functional association of rat testicular membrane-associated cytosolic glutathione S transferases and cyclooxygenase in vitro.
  Asian J Androl, 7, 171-178.  
16408039 V.E.Kagan, V.A.Tyurin, J.Jiang, Y.Y.Tyurina, V.B.Ritov, A.A.Amoscato, A.N.Osipov, N.A.Belikova, A.A.Kapralov, V.Kini, I.I.Vlasova, Q.Zhao, M.Zou, P.Di, D.A.Svistunenko, I.V.Kurnikov, and G.G.Borisenko (2005).
Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors.
  Nat Chem Biol, 1, 223-232.  
15078587 A.A.Cheema (2004).
Should people on aspirin avoid Ibuprofen? A review of the literature.
  Cardiol Rev, 12, 174-176.  
15198222 J.E.Wilson, N.V.Chandrasekharan, K.D.Westover, K.B.Eager, and D.L.Simmons (2004).
Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs.
  Am J Vet Res, 65, 810-818.  
15317588 K.Valmsen, W.E.Boeglin, I.Järving, C.Schneider, K.Varvas, A.R.Brash, and N.Samel (2004).
Structural and functional comparison of 15S- and 15R-specific cyclooxygenases from the coral Plexaura homomalla.
  Eur J Biochem, 271, 3533-3538.  
14668809 G.A.FitzGerald (2003).
COX-2 and beyond: Approaches to prostaglandin inhibition in human disease.
  Nat Rev Drug Discov, 2, 879-890.  
12598136 G.A.FitzGerald (2003).
Parsing an enigma: the pharmacodynamics of aspirin resistance.
  Lancet, 361, 542-544.  
12848292 K.Gawrisch, N.V.Eldho, and L.L.Holte (2003).
The structure of DHA in phospholipid membranes.
  Lipids, 38, 445-452.  
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.  
11941383 A.Szczeklik, E.Nizankowska, L.Mastalerz, and Z.Szabo (2002).
Analgesics and asthma.
  Am J Ther, 9, 233-243.  
11940059 A.Szczeklik, and M.Sanak (2002).
The role of COX-1 and COX-2 in asthma pathogenesis and its significance in the use of selective inhibitors.
  Clin Exp Allergy, 32, 339-342.  
11807164 L.J.Marnett, and R.N.DuBois (2002).
COX-2: a target for colon cancer prevention.
  Annu Rev Pharmacol Toxicol, 42, 55-80.  
11413151 C.N.Serhan, and E.Oliw (2001).
Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways.
  J Clin Invest, 107, 1481-1489.  
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.

 

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