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PDBsum entry 1pgg

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
1pgg
Jmol
Contents
Protein chains
551 a.a. *
Ligands
NAG ×4
NAG-NAG ×2
HEM ×2
IMM ×2
* Residue conservation analysis
PDB id:
1pgg
Name: Oxidoreductase
Title: Prostaglandin h2 synthase-1 complexed with 1-(4-iodobenzoyl) methoxy-2-methylindole-3-acetic acid (iodoindomethacin), tr
Structure: Prostaglandin h2 synthase-1. Chain: a, b. Synonym: cyclooxygenase i. Ec: 1.14.99.1
Source: Ovis aries. Sheep. Organism_taxid: 9940. Organelle: seminal vesicle
Biol. unit: Dimer (from PQS)
Resolution:
4.50Å     R-factor:   0.254     R-free:   0.267
Authors: P.J.Loll,D.Picot,R.M.Garavito
Key ref:
P.J.Loll et al. (1996). Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site. Biochemistry, 35, 7330-7340. PubMed id: 8652509 DOI: 10.1021/bi952776w
Date:
02-Dec-95     Release date:   11-Jan-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P05979  (PGH1_SHEEP) -  Prostaglandin G/H synthase 1
Seq:
Struc:
 
Seq:
Struc:
600 a.a.
551 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure
* 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!
  Cellular component     membrane   8 terms 
  Biological process     oxidation-reduction process   10 terms 
  Biochemical function     oxidoreductase activity     6 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi952776w Biochemistry 35:7330-7340 (1996)
PubMed id: 8652509  
 
 
Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site.
P.J.Loll, D.Picot, O.Ekabo, R.M.Garavito.
 
  ABSTRACT  
 
The cyclooxygenase activity of the membrane protein prostaglandin H2 synthase isoform 1 (PGHS-1) is the target of the nonsteroidal antiinflammatory drugs (NSAIDs). The X-ray crystal structures of PGHS-1 in complex with the NSAIDs flurbiprofen and bromoaspirin have been determined previously [Picot, D., et al. (1994) Nature 367, 243-249; Loll, P. J., et al. (1995) Nat. Struct. Biol. 2, 637-643]. We report here the preparation and characterization of novel potent iodinated analogs of the NSAIDs indomethacin and suprofen, as well as the refined X-ray crystal structures of their complexes with PGHS-1. The PGHS-iodosuprofen complex structure has been refined at 3.5 A to an R-value of 0.189 and shows the suprofen analog to share a common mode of binding with flurbiprofen. The PGHS-iodoindomethacin complex structure has been refined at 4.5 A to an R-value of 0.254. The low resolution of the iodoindomethacin complex structure precludes detailed modeling of drug-enzyme interactions, but the electron-dense iodine atom of the inhibitor has been unambiguously located, allowing for the placement and approximate orientation of the inhibitor in the enzyme's active site. We have modeled two equally likely binding modes for iodoindomethacin, corresponding to the two principal conformers of the inhibitor. Like flurbiprofen, iodosuprofen and iodoindomethacin bind at the end of the long channel which leads into the enzyme active site. Binding at this site presumably blocks access of substrate to Tyr-385, a residue essential for catalysis. No evidence is seen for significant protein conformational differences between the iodoindomethacin and iodosuprofen of flurbiprofen complex structures.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19433337 C.E.Rogge, W.Liu, R.J.Kulmacz, and A.L.Tsai (2009).
Peroxide-induced radical formation at TYR385 and TYR504 in human PGHS-1.
  J Inorg Biochem, 103, 912-922.  
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.  
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
17202703 N.Handler, W.Jaeger, H.Puschacher, K.Leisser, and T.Erker (2007).
Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors.
  Chem Pharm Bull (Tokyo), 55, 64-71.  
17305413 N.Moore (2007).
Diclofenac potassium 12.5mg tablets for mild to moderate pain and fever: a review of its pharmacology, clinical efficacy and safety.
  Clin Drug Investig, 27, 163-195.  
17131462 O.Cruz-López, J.J.Díaz-Mochón, J.M.Campos, A.Entrena, M.T.Núñez, L.Labeaga, A.Orjales, M.A.Gallo, and A.Espinosa (2007).
Design, Syntheses, Biological Evaluation, and Docking Studies of 2-Substituted 5-Methylsulfonyl-1-Phenyl-1H-Indoles: Potent and Selective in vitro Cyclooxygenase-2 Inhibitors.
  ChemMedChem, 2, 88.  
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.  
16855309 T.C.Terwilliger, H.Klei, P.D.Adams, N.W.Moriarty, and J.D.Cohn (2006).
Automated ligand fitting by core-fragment fitting and extension into density.
  Acta Crystallogr D Biol Crystallogr, 62, 915-922.  
16041838 B.Narayana, K.K.Vijaya Raj, B.V.Ashalatha, and N.S.Kumari (2005).
Synthesis of some new 2-(6-methoxy-2-naphthyl)- 5-aryl-1,3,4-oxadiazoles as possible non-steroidal anti-inflammatory and analgesic agents.
  Arch Pharm (Weinheim), 338, 373-377.  
16192763 E.Munsterhjelm, N.M.Munsterhjelm, T.T.Niemi, O.Ylikorkala, P.J.Neuvonen, and P.H.Rosenberg (2005).
Dose-dependent inhibition of platelet function by acetaminophen in healthy volunteers.
  Anesthesiology, 103, 712-717.  
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.  
15240491 D.A.Svistunenko, and C.E.Cooper (2004).
A new method of identifying the site of tyrosyl radicals in proteins.
  Biophys J, 87, 582-595.  
15355747 T.Kurth, C.H.Hennekens, J.E.Buring, and J.M.Gaziano (2004).
Aspirin, NSAIDs, and COX-2 inhibitors in cardiovascular disease: possible interactions and implications for treatment of rheumatoid arthritis.
  Curr Rheumatol Rep, 6, 351-356.  
12574066 R.M.Garavito, and A.M.Mulichak (2003).
The structure of mammalian cyclooxygenases.
  Annu Rev Biophys Biomol Struct, 32, 183-206.  
11807164 L.J.Marnett, and R.N.DuBois (2002).
COX-2: a target for colon cancer prevention.
  Annu Rev Pharmacol Toxicol, 42, 55-80.  
10639181 A.S.Kalgutkar, B.C.Crews, S.W.Rowlinson, A.B.Marnett, K.R.Kozak, R.P.Remmel, and L.J.Marnett (2000).
Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors.
  Proc Natl Acad Sci U S A, 97, 925-930.  
10988074 M.G.Malkowski, S.L.Ginell, W.L.Smith, and R.M.Garavito (2000).
The productive conformation of arachidonic acid bound to prostaglandin synthase.
  Science, 289, 1933-1937.
PDB code: 1diy
10692466 S.W.Rowlinson, B.C.Crews, D.C.Goodwin, C.Schneider, J.K.Gierse, and L.J.Marnett (2000).
Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete.
  J Biol Chem, 275, 6586-6591.  
  10338019 A.M.Dean, and F.M.Dean (1999).
Carbocations in the synthesis of prostaglandins by the cyclooxygenase of PGH synthase? A radical departure!
  Protein Sci, 8, 1087-1098.  
10542447 L.J.Marnett, and A.S.Kalgutkar (1999).
Cyclooxygenase 2 inhibitors: discovery, selectivity and the future.
  Trends Pharmacol Sci, 20, 465-469.  
10438452 L.J.Marnett, S.W.Rowlinson, D.C.Goodwin, A.S.Kalgutkar, and C.A.Lanzo (1999).
Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition.
  J Biol Chem, 274, 22903-22906.  
10570255 R.M.Garavito, and D.L.DeWitt (1999).
The cyclooxygenase isoforms: structural insights into the conversion of arachidonic acid to prostaglandins.
  Biochim Biophys Acta, 1441, 278-287.  
10438506 S.W.Rowlinson, B.C.Crews, C.A.Lanzo, and L.J.Marnett (1999).
The binding of arachidonic acid in the cyclooxygenase active site of mouse prostaglandin endoperoxide synthase-2 (COX-2). A putative L-shaped binding conformation utilizing the top channel region.
  J Biol Chem, 274, 23305-23310.  
9736921 L.J.Marnett, and A.S.Kalgutkar (1998).
Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents.
  Curr Opin Chem Biol, 2, 482-490.  
9488715 O.Y.So, L.E.Scarafia, A.Y.Mak, O.H.Callan, and D.C.Swinney (1998).
The dynamics of prostaglandin H synthases. Studies with prostaglandin h synthase 2 Y355F unmask mechanisms of time-dependent inhibition and allosteric activation.
  J Biol Chem, 273, 5801-5807.  
8901870 C.Luong, A.Miller, J.Barnett, J.Chow, C.Ramesha, and M.F.Browner (1996).
Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2.
  Nat Struct Biol, 3, 927-933.  
8901861 R.M.Garavito (1996).
The cyclooxygenase-2 structure: new drugs for an old target?
  Nat Struct Biol, 3, 897-901.  
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 codes are shown on the right.