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PDBsum entry 3pgh

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
3pgh
Jmol
Contents
Protein chains
552 a.a. *
Ligands
NAG ×12
HEM ×4
FLP ×4
* Residue conservation analysis
PDB id:
3pgh
Name: Oxidoreductase
Title: Cyclooxygenase-2 (prostaglandin synthase-2) complexed with a selective inhibitor, flurbiprofen
Structure: Cyclooxygenase-2. Chain: a, b, c, d. Synonym: prostaglandin synthase-2. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Cell_line: cultured sf21. Tissue: dermal. Cell: fibroblast. Cellular_location: endoplasmic reticulum. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Homo-Dimer (from PDB file)
Resolution:
2.50Å     R-factor:   0.236     R-free:   0.316
Authors: R.Kurumbail,W.Stallings
Key ref: R.G.Kurumbail et al. (1996). Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature, 384, 644-648. PubMed id: 8967954
Date:
18-Dec-96     Release date:   24-Dec-97    
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
* 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 = 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!
  Cellular component     protein complex   8 terms 
  Biological process     maintenance of blood-brain barrier   64 terms 
  Biochemical function     lipid binding     10 terms  

 

 
    reference    
 
 
Nature 384:644-648 (1996)
PubMed id: 8967954  
 
 
Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents.
R.G.Kurumbail, A.M.Stevens, J.K.Gierse, J.J.McDonald, R.A.Stegeman, J.Y.Pak, D.Gildehaus, J.M.Miyashiro, T.D.Penning, K.Seibert, P.C.Isakson, W.C.Stallings.
 
  ABSTRACT  
 
Prostaglandins and glucocorticoids are potent mediators of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibition of prostaglandin production. The pharmacological target of NSAIDs is cyclooxygenase (COX, also known as PGH synthase), which catalyses the first committed step in arachidonic-acid metabolism. Two isoforms of the membrane protein COX are known: COX-1, which is constitutively expressed in most tissues, is responsible for the physiological production of prostaglandins; and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, is responsible for the elevated production of prostaglandins during inflammation. The structure of ovine COX-1 complexed with several NSAIDs has been determined. Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 A resolution. These structures explain the structural basis for the selective inhibition of COX-2, and demonstrate some of the conformational changes associated with time-dependent inhibition.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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21053051 A.K.Malde, and A.E.Mark (2011).
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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).
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20673202 C.Rink, and S.Khanna (2011).
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21403766 J.M.Lü, C.E.Rogge, G.Wu, R.J.Kulmacz, W.A.van der Donk, and A.L.Tsai (2011).
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20673774 R.E.Hubbard (2011).
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20662079 S.L.Chen, D.X.Zhao, and Z.Z.Yang (2011).
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Preclinical evaluation of a gene therapy treatment for transitional cell carcinoma.
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19728984 A.L.Tsai, and R.J.Kulmacz (2010).
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21110338 D.Raffa, O.Migliara, B.Maggio, F.Plescia, S.Cascioferro, M.G.Cusimano, G.Tringali, C.Cannizzaro, and F.Plescia (2010).
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Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.
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PDB code: 3kk6
20541701 H.Zhou, W.Liu, Y.Su, Z.Wei, J.Liu, S.K.Kolluri, H.Wu, Y.Cao, J.Chen, Y.Wu, T.Yan, X.Cao, W.Gao, A.Molotkov, F.Jiang, W.G.Li, B.Lin, H.P.Zhang, J.Yu, S.P.Luo, J.Z.Zeng, G.Duester, P.Q.Huang, and X.K.Zhang (2010).
NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.
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Emerging role of cyclooxygenase isoforms in the control of gastrointestinal neuromuscular functions.
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20430759 M.J.Uddin, B.C.Crews, A.L.Blobaum, P.J.Kingsley, D.L.Gorden, J.O.McIntyre, L.M.Matrisian, K.Subbaramaiah, A.J.Dannenberg, D.W.Piston, and L.J.Marnett (2010).
Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents.
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20808785 P.Wang, H.W.Bai, and B.T.Zhu (2010).
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20564576 S.Alcaro, A.Artese, M.Botta, A.T.Zizzari, F.Orallo, F.Ortuso, S.Schenone, C.Brullo, and M.Yáñez (2010).
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PDB codes: 2zk6 3ads 3adt 3adu 3adv 3adw 3adx
20215464 V.Limongelli, M.Bonomi, L.Marinelli, F.L.Gervasio, A.Cavalli, E.Novellino, and M.Parrinello (2010).
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Peroxide-induced radical formation at TYR385 and TYR504 in human PGHS-1.
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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.
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19347867 D.Zhao, X.Zhang, Y.Guo, W.Tan, and D.Lin (2009).
Cyclooxygenase-2 Gly587Arg variant is associated with differential enzymatic activity and risk of esophageal squamous-cell carcinoma.
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Cyclooxygenase competitive inhibitors alter tyrosyl radical dynamics in prostaglandin H synthase-2.
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An effective docking strategy for virtual screening based on multi-objective optimization algorithm.
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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.
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Characterization of an AM404 analogue, N-(3-hydroxyphenyl)arachidonoylamide, as a substrate and inactivator of prostaglandin endoperoxide synthase.
  Biochemistry, 48, 12233-12241.  
19540763 R.Vardanyan, G.Vijay, G.S.Nichol, L.Liu, I.Kumarasinghe, P.Davis, T.Vanderah, F.Porreca, J.Lai, and V.J.Hruby (2009).
Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain.
  Bioorg Med Chem, 17, 5044-5053.  
19621084 S.K.Palaninathan, N.N.Mohamedmohaideen, E.Orlandini, G.Ortore, S.Nencetti, A.Lapucci, A.Rossello, J.S.Freundlich, and J.C.Sacchettini (2009).
Novel transthyretin amyloid fibril formation inhibitors: synthesis, biological evaluation, and X-ray structural analysis.
  PLoS One, 4, e6290.
PDB codes: 3glz 3gs0 3gs4 3gs7
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.
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A receptor-grounded approach to teaching nonsteroidal antiinflammatory drug chemistry and structure-activity relationships.
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20476924 A.Calin (2008).
Celecoxib and ankylosing spondylitis.
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18277013 A.Kimoto, A.Hanaoka, M.Sasamata, and K.Miyata (2008).
[Pre-clinical and clinical profiles of celecoxib, a new specific cyclooxygenase-2 inhibitor]
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18158247 A.Orjales, R.Mosquera, B.López, R.Olivera, L.Labeaga, and M.T.Núñez (2008).
Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors.
  Bioorg Med Chem, 16, 2183-2199.  
18529043 A.Sun, J.J.Yoon, Y.Yin, A.Prussia, Y.Yang, J.Min, R.K.Plemper, and J.P.Snyder (2008).
Potent non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase complex.
  J Med Chem, 51, 3731-3741.  
18250160 C.A.Rouzer, and L.J.Marnett (2008).
Non-redundant functions of cyclooxygenases: oxygenation of endocannabinoids.
  J Biol Chem, 283, 8065-8069.  
18300249 D.A.Pearlman, B.G.Rao, and P.Charifson (2008).
FURSMASA: a new approach to rapid scoring functions that uses a MD-averaged potential energy grid and a solvent-accessible surface area term with parameters GA fit to experimental data.
  Proteins, 71, 1519-1538.  
18849972 E.D.Garcin, A.S.Arvai, R.J.Rosenfeld, M.D.Kroeger, B.R.Crane, G.Andersson, G.Andrews, P.J.Hamley, P.R.Mallinder, D.J.Nicholls, S.A.St-Gallay, A.C.Tinker, N.P.Gensmantel, A.Mete, D.R.Cheshire, S.Connolly, D.J.Stuehr, A.Aberg, A.V.Wallace, J.A.Tainer, and E.D.Getzoff (2008).
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.
  Nat Chem Biol, 4, 700-707.
PDB codes: 3e65 3e67 3e68 3e6l 3e6n 3e6o 3e6t 3e7g 3e7i 3e7m 3e7s 3e7t 3eah 3eai 3ebd 3ebf 3ej8
17516427 E.Proschak, M.Rupp, S.Derksen, and G.Schneider (2008).
Shapelets: possibilities and limitations of shape-based virtual screening.
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18590695 K.H.Ruan, C.Wijaya, V.Cervantes, and J.Wu (2008).
Characterization of the prostaglandin H2 mimic: binding to the purified human thromboxane A2 receptor in solution.
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17950253 M.C.Byrns, S.Steckelbroeck, and T.M.Penning (2008).
An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies.
  Biochem Pharmacol, 75, 484-493.  
18633528 P.Singh, A.Mittal, S.Kaur, W.Holzer, and S.Kumar (2008).
2, 3-Diaryl-5-ethylsulfanylmethyltetrahydrofurans as a new class of COX-2 inhibitors and cytotoxic agents.
  Org Biomol Chem, 6, 2706-2712.  
18217215 R.D.Clark (2008).
A ligand's-eye view of protein binding.
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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.
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18083709 T.Ohnuma, S.Onaga, K.Murata, T.Taira, and E.Katoh (2008).
LysM domains from Pteris ryukyuensis chitinase-A: a stability study and characterization of the chitin-binding site.
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18976171 T.Yoshida, J.S.Park, K.Yokosuka, K.Jimbo, K.Yamada, K.Sato, and K.Nagata (2008).
Effect of a nonprotein bioactive agent on the reduction of cyclooxygenase-2 and tumor necrosis factor-alpha in human intervertebral disc cells in vitro.
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19000823 Y.H.Wu, T.P.Ko, R.T.Guo, S.M.Hu, L.M.Chuang, and A.H.Wang (2008).
Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2.
  Structure, 16, 1714-1723.
PDB codes: 2zb3 2zb4 2zb7 2zb8
17434872 A.L.Blobaum, and L.J.Marnett (2007).
Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib.
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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.
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17177291 A.Mancini, D.V.Jovanovic, Q.W.He, and J.A.Di Battista (2007).
Site-specific proteolysis of cyclooxygenase-2: a putative step in inflammatory prostaglandin E(2) biosynthesis.
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18159230 A.Peretz, N.Degani-Katzav, M.Talmon, E.Danieli, A.Gopin, E.Malka, R.Nachman, A.Raz, D.Shabat, and B.Attali (2007).
A tale of switched functions: from cyclooxygenase inhibition to m-channel modulation in new diphenylamine derivatives.
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17656360 C.A.Harman, M.V.Turman, K.R.Kozak, L.J.Marnett, W.L.Smith, and R.M.Garavito (2007).
Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides.
  J Biol Chem, 282, 28096-28105.
PDB codes: 2oye 2oyu
17300293 C.L.Santos, B.A.Medeiros, R.C.Palheta-Junior, G.M.Macedo, M.A.Nobre-e-Souza, L.E.Troncon, A.A.Santos, and M.H.Souza (2007).
Cyclooxygenase-2 inhibition increases gastric tone and delays gastric emptying in rats.
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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).
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17524979 C.Schneider, D.A.Pratt, N.A.Porter, and A.R.Brash (2007).
Control of oxygenation in lipoxygenase and cyclooxygenase catalysis.
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17552439 D.Little, S.L.Jones, and A.T.Blikslager (2007).
Cyclooxygenase (COX) inhibitors and the intestine.
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17882334 F.Mancia, and W.A.Hendrickson (2007).
Expression of recombinant G-protein coupled receptors for structural biology.
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In search of cyclooxygenase inhibitors, anti-Mycobacterium tuberculosis and anti-malarial drugs from Thai flora and microbes.
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COX-2 localization within plasma membrane caveolae-like structures in human lobular intraepithelial neoplasia of the breast.
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Studies on 1,2,4-triazole derivatives as potential anti-inflammatory agents.
  Arch Pharm (Weinheim), 340, 586-590.  
17462992 J.Liu, S.A.Seibold, C.J.Rieke, I.Song, R.I.Cukier, and W.L.Smith (2007).
Prostaglandin endoperoxide H synthases: peroxidase hydroperoxide specificity and cyclooxygenase activation.
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18233118 J.Wang, X.Zheng, Y.Yang, D.Drueckhammer, W.Yang, G.Verkhivker, and E.Wang (2007).
Quantifying intrinsic specificity: a potential complement to affinity in drug screening.
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Clinical pharmacology of celecoxib, a COX-2 selective inhibitor.
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17652088 K.Valmsen, W.E.Boeglin, R.Järving, I.Järving, K.Varvas, A.R.Brash, and N.Samel (2007).
A critical role of non-active site residues on cyclooxygenase helices 5 and 6 in the control of prostaglandin stereochemistry at carbon 15.
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A generalized born implicit-membrane representation compared to experimental insertion free energies.
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17541796 M.J.James, R.J.Cook-Johnson, and L.G.Cleland (2007).
Selective COX-2 inhibitors, eicosanoid synthesis and clinical outcomes: a case study of system failure.
  Lipids, 42, 779-785.  
17640491 M.Salimi, M.H.Ghahremani, N.Naderi, M.Amini, E.Salimi, M.Amanlou, K.Abdi, R.Salehi, and A.Shafiee (2007).
Design, synthesis and pharmacological evaluation of 4-[2-alkylthio-5(4)-(4-substitutedphenyl)imidazole-4(5)yl]benzenesulfonamides as selective COX-2 inhibitors.
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17202703 N.Handler, W.Jaeger, H.Puschacher, K.Leisser, and T.Erker (2007).
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PDB code: 1bl4
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PDB codes: 1amv 2amv
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