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PDBsum entry 1pth

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Oxidoreductase PDB id
1pth
Jmol
Contents
Protein chains
551 a.a. *
Ligands
NAG ×4
NAG-NAG ×2
BOG ×2
HEM ×2
SAL ×2
Waters ×1
* Residue conservation analysis
PDB id:
1pth
Name: Oxidoreductase
Title: The structural basis of aspirin activity inferred from thE C structure of inactivated prostaglandin h2 synthase
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 vesicles
Biol. unit: Dimer (from PQS)
Resolution:
3.40Å     R-factor:   0.186     R-free:   0.227
Authors: P.J.Loll,D.Picot,R.M.Garavito
Key ref: P.J.Loll et al. (1995). The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol, 2, 637-643. PubMed id: 7552725
Date:
11-Apr-95     Release date:   11-Apr-96    
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  CATH domain
* PDB and UniProt seqs differ at 3 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     membrane   8 terms 
  Biological process     oxidation-reduction process   10 terms 
  Biochemical function     oxidoreductase activity     6 terms  

 

 
    reference    
 
 
Nat Struct Biol 2:637-643 (1995)
PubMed id: 7552725  
 
 
The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.
P.J.Loll, D.Picot, R.M.Garavito.
 
  ABSTRACT  
 
Aspirin exerts its anti-inflammatory effects through selective acetylation of serine 530 on prostaglandin H2 synthase (PGHS). Here we present the 3.4 A resolution X-ray crystal structure of PGHS isoform-1 inactivated by the potent aspirin analogue 2-bromoacetoxy-benzoic acid. Acetylation by this analogue abolishes cyclooxygenase activity by steric blockage of the active-site channel and not through a large conformational change. We observe two rotameric states of the acetyl-serine side chain which block the channel to different extents, a result which may explain the dissimilar effects of aspirin on the two PGHS isoforms. We also observe the product salicylic acid binding at a site consistent with its antagonistic effect on aspirin activity.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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[In Process Citation]
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Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells.
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Acetylsalicylic acid induces programmed cell death in Arabidopsis cell cultures.
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17257477 A.Lanas, and J.Scheiman (2007).
Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment.
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Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions.
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17180149 C.Patrono, and B.Rocca (2007).
Drug insight: aspirin resistance--fact or fashion?
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17692387 G.A.Gale, K.Kirtikara, P.Pittayakhajonwut, S.Sivichai, Y.Thebtaranonth, C.Thongpanchang, and V.Vichai (2007).
In search of cyclooxygenase inhibitors, anti-Mycobacterium tuberculosis and anti-malarial drugs from Thai flora and microbes.
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17723122 G.de Gaetano, and C.Cerletti (2007).
Platelet function, antiplatelet therapy and clinical outcomes: to test or not to test?
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17429597 H.Neuss, X.Huang, B.K.Hetfeld, R.Deva, P.Henklein, S.Nigam, J.W.Mall, W.Schwenk, and W.Dubiel (2007).
The ubiquitin- and proteasome-dependent degradation of COX-2 is regulated by the COP9 signalosome and differentially influenced by coxibs.
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17392619 J.Ellison, and W.Dager (2007).
Recent FDA warning of the concomitant use of aspirin and ibuprofen and the effects on platelet aggregation.
  Prev Cardiol, 10, 61-63.  
17006962 A.E.Reynolds, and L.W.Enquist (2006).
Biological interactions between herpesviruses and cyclooxygenase enzymes.
  Rev Med Virol, 16, 393-403.  
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.  
19804092 U.S.Tantry, A.Etherington, K.P.Bliden, and P.A.Gurbel (2006).
Antiplatelet therapy: current strategies and future trends.
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16150050 A.O.Maree, R.J.Curtin, A.Chubb, C.Dolan, D.Cox, J.O'Brien, P.Crean, D.C.Shields, and D.J.Fitzgerald (2005).
Cyclooxygenase-1 haplotype modulates platelet response to aspirin.
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16149114 C.Drahl, B.F.Cravatt, and E.J.Sorensen (2005).
Protein-reactive natural products.
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15723265 C.Watala, J.Pluta, J.Golanski, M.Rozalski, M.Czyz, Z.Trojanowski, and J.Drzewoski (2005).
Increased protein glycation in diabetes mellitus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin.
  J Mol Med, 83, 148-158.  
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.  
15837265 M.L.Capone, M.G.Sciulli, S.Tacconelli, M.Grana, E.Ricciotti, G.Renda, P.Di Gregorio, G.Merciaro, and P.Patrignani (2005).
Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects.
  J Am Coll Cardiol, 45, 1295-1301.  
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.  
16197357 U.S.Tantry, K.P.Bliden, and P.A.Gurbel (2005).
Resistance to antiplatelet drugs: current status and future research.
  Expert Opin Pharmacother, 6, 2027-2045.  
15505497 A.C.Nulton-Persson, L.I.Szweda, and H.A.Sadek (2004).
Inhibition of cardiac mitochondrial respiration by salicylic acid and acetylsalicylate.
  J Cardiovasc Pharmacol, 44, 591-595.  
15492769 C.Nobles-James, E.A.James, and J.R.Sowers (2004).
Prevention of cardiovascular complications of diabetes mellitus by aspirin.
  Cardiovasc Drug Rev, 22, 215-226.  
14970279 E.T.Chang, T.Zheng, E.G.Weir, M.Borowitz, R.B.Mann, D.Spiegelman, and N.E.Mueller (2004).
Aspirin and the risk of Hodgkin's lymphoma in a population-based case-control study.
  J Natl Cancer Inst, 96, 305-315.  
15057273 M.Koch, C.Breithaupt, R.Kiefersauer, J.Freigang, R.Huber, and A.Messerschmidt (2004).
Crystal structure of protoporphyrinogen IX oxidase: a key enzyme in haem and chlorophyll biosynthesis.
  EMBO J, 23, 1720-1728.
PDB code: 1sez
15358034 R.I.Levin (2004).
Theriac found? Nitric oxide-aspirin and the search for the universal cure.
  J Am Coll Cardiol, 44, 642-643.  
15525992 R.Thoma, T.Schulz-Gasch, B.D'Arcy, J.Benz, J.Aebi, H.Dehmlow, M.Hennig, M.Stihle, and A.Ruf (2004).
Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase.
  Nature, 432, 118-122.
PDB codes: 1w6j 1w6k
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.  
14668809 G.A.FitzGerald (2003).
COX-2 and beyond: Approaches to prostaglandin inhibition in human disease.
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12941050 G.De Gaetano, and C.Cerletti (2003).
Aspirin resistance: a revival of platelet aggregation tests?
  J Thromb Haemost, 1, 2048-2050.  
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Clinical pharmacology of etoricoxib: a novel selective COX2 inhibitor.
  Expert Opin Pharmacother, 4, 265-284.  
12574066 R.M.Garavito, and A.M.Mulichak (2003).
The structure of mammalian cyclooxygenases.
  Annu Rev Biophys Biomol Struct, 32, 183-206.  
12960371 S.Fiorucci, L.Santucci, J.L.Wallace, M.Sardina, M.Romano, P.del Soldato, and A.Morelli (2003).
Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa.
  Proc Natl Acad Sci U S A, 100, 10937-10941.  
12197849 A.Van Hecken, M.L.Juliano, M.Depré, I.De Lepeleire, J.Arnout, A.Dynder, L.Wildonger, K.J.Petty, K.Gottesdiener, and J.N.De Hoon (2002).
Effects of enteric-coated, low-dose aspirin on parameters of platelet function.
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11977450 H.Ulbrich, and G.Dannhardt (2002).
[A heterogenous drug class. NSAID: classification and spectrum of action]
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11807164 L.J.Marnett, and R.N.DuBois (2002).
COX-2: a target for colon cancer prevention.
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Cyclooxygenase-2 inhibitors: promise or peril?
  Mediators Inflamm, 11, 275-286.  
12357134 P.Mehta (2002).
Aspirin in the prophylaxis of coronary artery disease.
  Curr Opin Cardiol, 17, 552-558.  
12011329 T.Grosser, S.Yusuff, E.Cheskis, M.A.Pack, and G.A.FitzGerald (2002).
Developmental expression of functional cyclooxygenases in zebrafish.
  Proc Natl Acad Sci U S A, 99, 8418-8423.  
11390412 G.A.FitzGerald, and P.Loll (2001).
COX in a crystal ball: current status and future promise of prostaglandin research.
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11794538 H.S.Gwak, and I.K.Chun (2001).
Effect of vehicles and enhancers on the in vitro skin penetration of aspalatone and its enzymatic degradation across rat skins.
  Arch Pharm Res, 24, 572-577.  
11717412 M.Ouellet, D.Riendeau, and M.D.Percival (2001).
A high level of cyclooxygenase-2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin.
  Proc Natl Acad Sci U S A, 98, 14583-14588.  
10671506 C.Schneider, and A.R.Brash (2000).
Stereospecificity of hydrogen abstraction in the conversion of arachidonic acid to 15R-HETE by aspirin-treated cyclooxygenase-2. Implications for the alignment of substrate in the active site.
  J Biol Chem, 275, 4743-4746.  
11113025 D.L.Simmons, D.Wagner, and K.Westover (2000).
Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever.
  Clin Infect Dis, 31, S211-S218.  
10722687 E.D.Thuresson, K.M.Lakkides, and W.L.Smith (2000).
Different catalytically competent arrangements of arachidonic acid within the cyclooxygenase active site of prostaglandin endoperoxide H synthase-1 lead to the formation of different oxygenated products.
  J Biol Chem, 275, 8501-8507.  
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.  
10966456 W.L.Smith, D.L.DeWitt, and R.M.Garavito (2000).
Cyclooxygenases: structural, cellular, and molecular biology.
  Annu Rev Biochem, 69, 145-182.  
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Carbocations in the synthesis of prostaglandins by the cyclooxygenase of PGH synthase? A radical departure!
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10358065 C.J.Rieke, A.M.Mulichak, R.M.Garavito, and W.L.Smith (1999).
The role of arginine 120 of human prostaglandin endoperoxide H synthase-2 in the interaction with fatty acid substrates and inhibitors.
  J Biol Chem, 274, 17109-17114.  
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Substitution, insertion, deletion, suppression, and altered substrate specificity in functional protocatechuate 3,4-dioxygenases.
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Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs.
  Proc Natl Acad Sci U S A, 96, 3275-3280.  
10542447 L.J.Marnett, and A.S.Kalgutkar (1999).
Cyclooxygenase 2 inhibitors: discovery, selectivity and the future.
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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.
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10477832 M.Rosenstock, A.Danon, and G.Rimon (1999).
PGHS-2 inhibitors, NS-398 and DuP-697, attenuate the inhibition of PGHS-1 by aspirin and indomethacin without altering its activity.
  Biochim Biophys Acta, 1440, 127-137.  
10570255 R.M.Garavito, and D.L.DeWitt (1999).
The cyclooxygenase isoforms: structural insights into the conversion of arachidonic acid to prostaglandins.
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Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents.
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9263636 J.Taunton (1997).
How to starve a tumor.
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8652509 P.J.Loll, D.Picot, O.Ekabo, and R.M.Garavito (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.
PDB codes: 1pge 1pgf 1pgg
8901861 R.M.Garavito (1996).
The cyclooxygenase-2 structure: new drugs for an old target?
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8718891 V.Houtzager, M.Ouellet, J.P.Falgueyret, L.A.Passmore, C.Bayly, and M.D.Percival (1996).
Inhibitor-induced changes in the intrinsic fluorescence of human cyclooxygenase-2.
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Cyclooxygenase-2 and its regulation in inflammation.
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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.