PDBsum entry 1iyi

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Isomerase PDB id
Jmol PyMol
Protein chain
198 a.a. *
GSH ×4
_CA ×2
Waters ×1089
* Residue conservation analysis
PDB id:
Name: Isomerase
Title: Crystal structure of hematopoietic prostaglandin d synthase
Structure: Hematopoietic prostaglandin d synthase. Chain: a, b, c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
1.80Å     R-factor:   0.188     R-free:   0.220
Authors: T.Inoue
Key ref:
T.Inoue et al. (2003). Mechanism of metal activation of human hematopoietic prostaglandin D synthase. Nat Struct Biol, 10, 291-296. PubMed id: 12627223 DOI: 10.1038/nsb907
26-Aug-02     Release date:   08-Apr-03    
Go to PROCHECK summary

Protein chains
-  (POLG_HAVHM) - 
Protein chains
Pfam   ArchSchema ?
O60760  (HPGDS_HUMAN) -  Hematopoietic prostaglandin D synthase
199 a.a.
198 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 2: E.C.  - Glutathione transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RX + glutathione = HX + R-S-glutathione
Bound ligand (Het Group name = GSH)
corresponds exactly
= HX
+ R-S-glutathione
   Enzyme class 3: E.C.  - Prostaglandin-D synthase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (5Z,13E,15S)-9-alpha,11-alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-9-alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
= (5Z,13E,15S)-9-alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
      Cofactor: Glutathione
Bound ligand (Het Group name = GSH) corresponds exactly
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   2 terms 
  Biological process     lipid metabolic process   10 terms 
  Biochemical function     protein binding     9 terms  


DOI no: 10.1038/nsb907 Nat Struct Biol 10:291-296 (2003)
PubMed id: 12627223  
Mechanism of metal activation of human hematopoietic prostaglandin D synthase.
T.Inoue, D.Irikura, N.Okazaki, S.Kinugasa, H.Matsumura, N.Uodome, M.Yamamoto, T.Kumasaka, M.Miyano, Y.Kai, Y.Urade.
Here we report the crystal structures of human hematopoietic prostaglandin (PG) D synthase bound to glutathione (GSH) and Ca2+ or Mg2+. Using GSH as a cofactor, prostaglandin D synthase catalyzes the isomerization of PGH2 to PGD2, a mediator for allergy response. The enzyme is a homodimer, and Ca2+ or Mg2+ increases its activity to approximately 150% of the basal level, with half maximum effective concentrations of 400 microM for Ca2+ and 50 microM for Mg2+. In the Mg2+-bound form, the ion is octahedrally coordinated by six water molecules at the dimer interface. The water molecules are surrounded by pairs of Asp93, Asp96 and Asp97 from each subunit. Ca(2+) is coordinated by five water molecules and an Asp96 from one subunit. The Asp96 residue in the Ca2+-bound form makes hydrogen bonds with two guanidium nitrogen atoms of Arg14 in the GSH-binding pocket. Mg2+ alters the coordinating water structure and reduces one hydrogen bond between Asp96 and Arg14, thereby changing the interaction between Arg14 and GSH. This effect explains a four-fold reduction in the K(m) of the enzyme for GSH. The structure provides insights into how Ca2+ or Mg2+ binding activates human hematopoietic PGD synthase.
  Selected figure(s)  
Figure 2.
Figure 2. The metal coordination structures of human H-PGDS. a, The Ca^2+-bound form. b, Mg2+-bound form. The 2F[o] - F[c] map is contoured at the 1.0 level around the metal ion, and the designation for each subunit is given in parentheses. c, Superposition of the Mg2+- and Ca^2+-binding site. The water coordination structure in the Mg2+- and Ca^2+-bound forms (purple and gray, respectively) are different. The hydrogen bond between N2(Arg14) and O2(Asp96) is lost in the Mg2+-bound form, and its average distance has increased from 2.90 to 3.66 . d, A schematic drawing of the effect of metal ion on the reaction. The superimposed structures of the active site of the Ca^2+- and Mg2+-bound forms are shown with ball-and-stick models and viewed in the same direction as in Fig. 1d. Only Asp96 and Arg14 (purple) change their position upon binding of Mg2+. The distance between N (Arg14) and S of GSH (green) decreases from 4.56 in the Ca^2+ form to 4.26 in the Mg2+ form. The binding model for the substrate, PGH[2], was previously proposed^7, 15, 16. The energy-minimized model of PGH[2] was calculated using CNS27. When the amide nitrogen of glycine in GSH accesses and interacts with O9 of the endoperoxide group of the substrate, the activated thiol of GSH can attack O11 of the endoperoxide group.
Figure 3.
Figure 3. Effect of metal ion on the PGDS activity. a, The activity with 0.04 mM PGH[2]. b, The activity with an excess (2 mM) of GSH. The measurements were performed in the presence or absence of Ca^2+ or Mg2+. 'None' indicates measurement in 1 mM EDTA and EGTA. c, Comparison of the amino acid sequence around helix 5. Human H-PGDS (GenBank AB045398), rat H-PGDS (GenBank D82071), chicken H-PGDS (GenBank AJ006405), squid -GST (SWISS-PROT P46088), human -GST (GenBank M15872), human -GST (GenBank M96234) and human -GST (GenBank X06547) are shown. Three aspartates (Asp93, Asp96 and Asp97) are conserved among all H-PGDS and acquire the metal activation. d, Effects of mutation on metal activation. The activity for each wild type and the D93N, D96N and D97N mutants is shown. The first three columns show measurements carried out with 0.1 mM GSH; and the second three columns, with 2 mM GSH. Each set of three columns contains the activity under 1 mM EDTA and 2 mM CaCl[2] or 2 mM MgCl[2].
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 291-296) copyright 2003.  
  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.  
  21425928 J.U.Flanagan, and M.L.Smythe (2011).
Sigma-class glutathione transferases.
  Drug Metab Rev, 43, 194-214.  
20122226 P.Paragi-Vedanthi, and M.Doble (2010).
Comparison of PGH2 binding site in prostaglandin synthases.
  BMC Bioinformatics, 11, S51.  
19131342 D.Irikura, K.Aritake, N.Nagata, T.Maruyama, S.Shimamoto, and Y.Urade (2009).
Biochemical, Functional, and Pharmacological Characterization of AT-56, an Orally Active and Selective Inhibitor of Lipocalin-type Prostaglandin D Synthase.
  J Biol Chem, 284, 7623-7630.  
  19359520 I.Mohri, K.Aritake, H.Taniguchi, Y.Sato, S.Kamauchi, N.Nagata, T.Maruyama, M.Taniike, and Y.Urade (2009).
Inhibition of prostaglandin D synthase suppresses muscular necrosis.
  Am J Pathol, 174, 1735-1744.  
17594497 O.A.Asojo, K.Homma, M.Sedlacek, M.Ngamelue, G.N.Goud, B.Zhan, V.Deumic, O.Asojo, and P.J.Hotez (2007).
X-ray structures of Na-GST-1 and Na-GST-2 two glutathione S-transferase from the human hookworm Necator americanus.
  BMC Struct Biol, 7, 42.
PDB codes: 2on5 2on7
16310861 J.L.Herlong, and T.R.Scott (2006).
Positioning prostanoids of the D and J series in the immunopathogenic scheme.
  Immunol Lett, 102, 121-131.  
16547010 K.Aritake, Y.Kado, T.Inoue, M.Miyano, and Y.Urade (2006).
Structural and functional characterization of HQL-79, an orally selective inhibitor of human hematopoietic prostaglandin D synthase.
  J Biol Chem, 281, 15277-15286.
PDB code: 2cvd
16189827 D.J.Schuller, Q.Liu, I.A.Kriksunov, A.M.Campbell, J.Barrett, P.M.Brophy, and Q.Hao (2005).
Crystal structure of a new class of glutathione transferase from the model human hookworm nematode Heligmosomoides polygyrus.
  Proteins, 61, 1024-1031.
PDB code: 1tw9
14695453 Y.Urade, N.Eguchi, K.Aritake, and O.Hayaishi (2004).
[Functional analyses of lipocalin-type and hematopoietic prostaglandin D synthases]
  Nippon Yakurigaku Zasshi, 123, 5.  
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.