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PDBsum entry 1z9h

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protein ligands metals Protein-protein interface(s) links
Isomerase PDB id
1z9h
Jmol
Contents
Protein chains
274 a.a. *
Ligands
ACT ×4
IMN ×4
Metals
_CL ×4
Waters ×88
* Residue conservation analysis
PDB id:
1z9h
Name: Isomerase
Title: Microsomal prostaglandin e synthase type-2
Structure: Membrane-associated prostaglandin e synthase-2. Chain: a, b, c, d. Engineered: yes
Source: Macaca fascicularis. Crab-eating macaque. Organism_taxid: 9541. Tissue: brain. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
2.60Å     R-factor:   0.214     R-free:   0.251
Authors: T.Yamada,J.Komoto,K.Watanabe,Y.Ohmiya,F.Takusagawa
Key ref:
T.Yamada et al. (2005). Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2). J Mol Biol, 348, 1163-1176. PubMed id: 15854652 DOI: 10.1016/j.jmb.2005.03.035
Date:
02-Apr-05     Release date:   17-May-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q9N0A4  (PGES2_MACFA) -  Prostaglandin E synthase 2
Seq:
Struc:
377 a.a.
274 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.5.3.99.3  - Prostaglandin-E synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (5Z,13E)-(15S)-9-alpha,11-alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E)-(15S)-11-alpha,15-dihydroxy-9-oxoprosta-5,13-dienoate
(5Z,13E)-(15S)-9-alpha,11-alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
= (5Z,13E)-(15S)-11-alpha,15-dihydroxy-9-oxoprosta-5,13-dienoate
      Cofactor: Glutathione
Glutathione
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     cell redox homeostasis   1 term 
  Biochemical function     electron carrier activity     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.jmb.2005.03.035 J Mol Biol 348:1163-1176 (2005)
PubMed id: 15854652  
 
 
Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2).
T.Yamada, J.Komoto, K.Watanabe, Y.Ohmiya, F.Takusagawa.
 
  ABSTRACT  
 
Prostaglandin (PG) H(2) (PGH(2)), formed from arachidonic acid, is an unstable intermediate and is converted efficiently into more stable arachidonate metabolites (PGD(2), PGE(2), and PGF(2)) by the action of three groups of enzymes. Prostaglandin E synthase catalyzes an isomerization reaction, PGH(2) to PGE(2). Microsomal prostaglandin E synthase type-2 (mPGES-2) has been crystallized with an anti-inflammatory drug indomethacin (IMN), and the complex structure has been determined at 2.6A resolution. mPGES-2 forms a dimer and is attached to lipid membrane by anchoring the N-terminal section. Two hydrophobic pockets connected to form a V shape are located in the bottom of a large cavity. IMN binds deeply in the cavity by placing the OMe-indole and chlorophenyl moieties into the V-shaped pockets, respectively, and the carboxyl group interacts with S(gamma) of C110 by forming a H-bond. A characteristic H-bond chain formation (N-H...S(gamma)-H...S(gamma)...H-N) is seen through Y107-C113-C110-F112, which apparently decreases the pK(a) of S(gamma) of C110. The geometry suggests that the S(gamma) of C110 is most likely the catalytic site of mPGES-2. A search of the RCSB Protein Data Bank suggests that IMN can fit into the PGH(2) binding site in various proteins. On the basis of the crystal structure and mutation data, a PGH(2)-bound model structure was built. PGH(2) fits well into the IMN binding site by placing the alpha and omega-chains in the V-shaped pockets, and the endoperoxide moiety interacts with S(gamma) of C110. A possible catalytic mechanism is proposed on the basis of the crystal and model structures, and an alternative catalytic mechanism is described. The fold of mPGES-2 is quite similar to those of GSH-dependent hematopoietic prostaglandin D synthase, except for the two large loop sections.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Topology diagram. The circles and triangles represent a-helix and b-strand, respectively. The triangle, open and triangle, open indicate the upward and downward direction of the b-strand, respectively. The amino acid residues in the secondary structure are: b1(101-106)-a1(111-122)-b2(126-132)-a2(138-140)-b3(150-155)-b4(158-162)-a3(165-178)-a4(182-188)-b5(190-196)-b6(200-206)-a5(214-221)-a6(224-240)-a7(243-250)-a8(254-267)-a9(272-296)-a10(303-318)-a11(332-342)-a12(348-355)-a13(360-370).
Figure 6.
Figure 6. An alternative catalytic mechanism. A PGH[2] molecule binds in the cavity of mPGES-2 by locating C[9] in the C110 catalytic bowl, while the carboxyl group of the a-chain interacts with a positively charged region where H241, H244, R292, and R296 are located. The deprotonated Sg of C110 abstracts the hydrogen atom attached to C[9], and the O[9]-O[11] bond is cleaved by acid catalysis by a water molecule or R-SH.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 348, 1163-1176) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21428697 A.Oakley (2011).
Glutathione transferases: a structural perspective.
  Drug Metab Rev, 43, 138-151.  
21478637 H.Fujino, and T.Murayama (2011).
[Novel anti-cancer effects of indomethacin: exploring the cyclooxygenase-inhibition-independent effects].
  Nippon Yakurigaku Zasshi, 137, 177-181.  
  21425928 J.U.Flanagan, and M.L.Smythe (2011).
Sigma-class glutathione transferases.
  Drug Metab Rev, 43, 194-214.  
20369883 A.Hamza, M.Tong, M.D.AbdulHameed, J.Liu, A.C.Goren, H.H.Tai, and C.G.Zhan (2010).
Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis.
  J Phys Chem B, 114, 5605-5616.  
20122226 P.Paragi-Vedanthi, and M.Doble (2010).
Comparison of PGH2 binding site in prostaglandin synthases.
  BMC Bioinformatics, 11, S51.  
18777160 L.Xing, R.G.Kurumbail, R.B.Frazier, M.S.Davies, H.Fujiwara, R.A.Weinberg, J.K.Gierse, N.Caspers, J.S.Carter, J.J.McDonald, W.M.Moore, and M.L.Vazquez (2009).
Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions.
  J Comput Aided Mol Des, 23, 13-24.  
19244215 M.W.Buczynski, D.S.Dumlao, and E.A.Dennis (2009).
Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology.
  J Lipid Res, 50, 1015-1038.  
18682561 C.Jegerschöld, S.C.Pawelzik, P.Purhonen, P.Bhakat, K.R.Gheorghe, N.Gyobu, K.Mitsuoka, R.Morgenstern, P.J.Jakobsson, and H.Hebert (2008).
Structural basis for induced formation of the inflammatory mediator prostaglandin E2.
  Proc Natl Acad Sci U S A, 105, 11110-11115.
PDB code: 3dww
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
17603894 A.L.Lomize, I.D.Pogozheva, M.A.Lomize, and H.I.Mosberg (2007).
The role of hydrophobic interactions in positioning of peripheral proteins in membranes.
  BMC Struct Biol, 7, 44.  
17329938 J.C.Yao, W.G.Duan, Y.Yun, d.e. .Q.Liu, M.Yan, Z.Z.Jiang, and L.Y.Zhang (2007).
Screening method for nonsteroidal antiinflammatory drugs based on the cyclooxygenase 2 pathway activated by serum-free stimulation in A549 cells.
  Yakugaku Zasshi, 127, 527-532.  
17978563 Y.Yun, P.Chen, C.L.Zheng, Y.Yang, W.G.Duan, L.Wang, B.He, J.Q.Ma, D.H.Wang, and Z.Q.Shen (2007).
Copper-aspirin complex inhibits cyclooxygenase-2 more selectively than aspirin.
  Yakugaku Zasshi, 127, 1869-1875.  
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.