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PDBsum entry 2vd1

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protein ligands metals Protein-protein interface(s) links
Isomerase PDB id
2vd1
Jmol
Contents
Protein chains
198 a.a. *
183 a.a. *
Ligands
GSH ×4
D28
Metals
_MG
Waters ×349
* Residue conservation analysis
PDB id:
2vd1
Name: Isomerase
Title: Complex structure of prostaglandin d2 synthase at 2.25a.
Structure: Glutathione-requiring prostaglandin d synthase. Chain: a, b, c, d. Synonym: glutathione-dependent pgd synthetase, prostaglandin-h2 d-isomerase, hematopoietic prostaglandin d synthase, h-pgds, prostaglandin d2 synthase. Engineered: yes. Other_details: the protein contain a glutathione co-factor.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
2.25Å     R-factor:   0.188     R-free:   0.255
Authors: M.Hohwy,L.Spadola,B.Lundquist,K.Von Wachenfeldt, S.Persdotter,P.Hawtin,J.Dahmen,I.Groth-Clausen, R.H.A.Folmer,K.Edman
Key ref: M.Hohwy et al. (2008). Novel prostaglandin D synthase inhibitors generated by fragment-based drug design. J Med Chem, 51, 2178-2186. PubMed id: 18341273 DOI: 10.1021/jm701509k
Date:
28-Sep-07     Release date:   15-Apr-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O60760  (HPGDS_HUMAN) -  Hematopoietic prostaglandin D synthase
Seq:
Struc:
199 a.a.
198 a.a.
Protein chain
Pfam   ArchSchema ?
O60760  (HPGDS_HUMAN) -  Hematopoietic prostaglandin D synthase
Seq:
Struc:
199 a.a.
183 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: Chains A, B, C, D: E.C.2.5.1.18  - Glutathione transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RX + glutathione = HX + R-S-glutathione
RX
+
glutathione
Bound ligand (Het Group name = GSH)
corresponds exactly
= HX
+ R-S-glutathione
   Enzyme class 3: Chains A, B, C, D: E.C.5.3.99.2  - 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,11-alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
= (5Z,13E,15S)-9-alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
      Cofactor: Glutathione
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     small molecule metabolic process   12 terms 
  Biochemical function     transferase activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm701509k J Med Chem 51:2178-2186 (2008)
PubMed id: 18341273  
 
 
Novel prostaglandin D synthase inhibitors generated by fragment-based drug design.
M.Hohwy, L.Spadola, B.Lundquist, P.Hawtin, J.Dahmén, I.Groth-Clausen, E.Nilsson, S.Persdotter, K.von Wachenfeldt, R.H.Folmer, K.Edman.
 
  ABSTRACT  
 
We describe the discovery of novel inhibitors of prostaglandin D2 synthase (PGDS) through fragment-based lead generation and structure-based drug design. A library of 2500 low-molecular-weight compounds was screened using 2D nuclear magnetic resonance (NMR), leading to the identification of 24 primary hits. Structure determination of protein-ligand complexes with the hits enabled a hit optimization process, whereby we harvested increasingly more potent inhibitors out of our corporate compound collection. Two iterative cycles were carried out, comprising NMR screening, molecular modeling, X-ray crystallography, and in vitro biochemical testing. Six novel high-resolution PGDS complex structures were determined, and 300 hit analogues were tested. This rational drug design procedure culminated in the discovery of 24 compounds with an IC 50 below 1 microM in the in vitro assay. The best inhibitor (IC 50 = 21 nM) is one of the most potent inhibitors of PGDS to date. As such, it may enable new functional in vivo studies of PGDS and the prostaglandin metabolism pathway.
 

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.  
20223699 A.G.Coyne, D.E.Scott, and C.Abell (2010).
Drugging challenging targets using fragment-based approaches.
  Curr Opin Chem Biol, 14, 299-307.  
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
  20606289 S.Takahashi, T.Tsurumura, K.Aritake, N.Furubayashi, M.Sato, M.Yamanaka, E.Hirota, S.Sano, T.Kobayashi, T.Tanaka, K.Inaka, H.Tanaka, and Y.Urade (2010).
High-quality crystals of human haematopoietic prostaglandin D synthase with novel inhibitors.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 66, 846-850.  
19443265 G.E.de Kloe, D.Bailey, R.Leurs, and I.J.de Esch (2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
  Drug Discov Today, 14, 630-646.  
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.