PDBsum entry 2aaw

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Transferase PDB id
Protein chains
205 a.a. *
GTX ×2
P33 ×2
Waters ×189
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Studies on ligand binding and enzyme inhibition of plasmodium falciparum glutathione s-transferase
Structure: Glutathione s-transferase. Chain: a, c. Engineered: yes
Source: Plasmodium falciparum. Malaria parasite p. Falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
2.40Å     R-factor:   0.194     R-free:   0.237
Authors: N.Hiller,K.Fritz-Wolf,M.Deponte,W.Wende,H.Zimmermann, K.Becker
Key ref:
N.Hiller et al. (2006). Plasmodium falciparum glutathione S-transferase--structural and mechanistic studies on ligand binding and enzyme inhibition. Protein Sci, 15, 281-289. PubMed id: 16385005 DOI: 10.1110/ps.051891106
14-Jul-05     Release date:   10-Jan-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q8MU52  (GST_PLAFA) -  Glutathione S-transferase
211 a.a.
205 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Glutathione transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RX + glutathione = HX + R-S-glutathione
Bound ligand (Het Group name = GTX)
matches with 76.00% similarity
= HX
+ R-S-glutathione
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   1 term 
  Biochemical function     transferase activity     2 terms  


DOI no: 10.1110/ps.051891106 Protein Sci 15:281-289 (2006)
PubMed id: 16385005  
Plasmodium falciparum glutathione S-transferase--structural and mechanistic studies on ligand binding and enzyme inhibition.
N.Hiller, K.Fritz-Wolf, M.Deponte, W.Wende, H.Zimmermann, K.Becker.
Glutathione S-transferase of the malarial parasite Plasmodium falciparum (PfGST) represents a novel class of GST isoenzymes. Since the architecture of the PfGST substrate binding site differs significantly from its human counterparts and there is only this one isoenzyme present in the parasite, PfGST is considered a highly attractive target for antimalarial drug development. Here we report the mechanistic, kinetic, and structural characterization of PfGST as well as its interaction with different ligands. Our data indicate that in solution PfGST is present as a tetramer that dissociates into dimers in the presence of glutathione (GSH). Fluorescence spectroscopy shows that in the presence of GSH GST serves as ligandin for parasitotoxic ferriprotoporphyrin IX with a high- and a low-affinity binding site. This is supported by a clear uncompetitive inhibition type. Site-directed mutagenesis studies demonstrate that neither Cys 86 nor Cys 101 contribute to the peroxidase activity of the enzyme, which is thus performed GSH-dependently at the active site. Tyr 9 is responsible for the deprotonation of GSH and Lys 15, but also Gln 71 are involved in GSH binding. We furthermore report the 2.4 A resolution X-ray structure of PfGST cocrystallized with the inhibitor S-hexylglutathione. In comparison with a previously reported structure obtained by crystal soaking, differences occur at the C-terminal end of helix alpha4 and at the S-hexylmoiety of the inhibitor. We furthermore show that, in contrast to previous reports, the antimalarial drug artemisinin is not metabolized by PfGST.
  Selected figure(s)  
Figure 1.
Structural comparison of GST enzymes. Superposition of the enzyme --inhibitor structures of PfGST (yellow), mu-class human GST (red, 1c72), and pi-class human GST (blue, 11gs). All inhibitors are drawn in ball and stick, with oxygens red and nitrogens blue. PfGST with bound S-hexylglutathione and a polyethylene glycol (PEG) molecule (carbons: yellow). Human mu-class GST with a bound glutathione conjugate (1-hydroxy-2-S-glutathionyl-3-paranitrophenoxypropane) (carbons: red). Human pi-class GST with the bound glutathione conjugate of ethacrynic acid (carbons: blue). The figure was drawn using the programs molscript and raster3d (Kraulis 1991; Merritt and Bacon 1997).
Figure 3.
Inhibition of PfGST by ferriprotoporphyrin IX. The parallel lines in a Dixon plot indicate an uncompetitive inhibition type of PfGST by FP. The corresponding Cornish-Bowden diagram ([S]/v against [I]) yields a K[i] value of 3 [mu]M (data not shown).
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2006, 15, 281-289) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20066034 D.Seeliger, and Groot (2010).
Conformational transitions upon ligand binding: holo-structure prediction from apo conformations.
  PLoS Comput Biol, 6, e1000634.  
19531494 E.Liebau, K.F.Dawood, R.Fabrini, L.Fischer-Riepe, M.Perbandt, L.Stella, J.Z.Pedersen, A.Bocedi, P.Petrarca, G.Federici, and G.Ricci (2009).
Tetramerization and cooperativity in Plasmodium falciparum glutathione S-transferase are mediated by atypic loop 113-119.
  J Biol Chem, 284, 22133-22139.  
19586953 E.Oksanen, M.P.Blakeley, F.Bonneté, M.T.Dauvergne, F.Dauvergne, and M.Budayova-Spano (2009).
Large crystal growth by thermal control allows combined X-ray and neutron crystallographic studies to elucidate the protonation states in Aspergillus flavus urate oxidase.
  J R Soc Interface, 6, S599-S610.  
19360125 N.Sturm, E.Jortzik, B.M.Mailu, S.Koncarevic, M.Deponte, K.Forchhammer, S.Rahlfs, and K.Becker (2009).
Identification of proteins targeted by the thioredoxin superfamily in Plasmodium falciparum.
  PLoS Pathog, 5, e1000383.  
19015351 N.Sturm, Y.Hu, H.Zimmermann, K.Fritz-Wolf, S.Wittlin, S.Rahlfs, and K.Becker (2009).
Compounds structurally related to ellagic acid show improved antiplasmodial activity.
  Antimicrob Agents Chemother, 53, 622-630.  
19806191 V.Gallo, E.Schwarzer, S.Rahlfs, R.H.Schirmer, R.van Zwieten, D.Roos, P.Arese, and K.Becker (2009).
Inherited glutathione reductase deficiency and Plasmodium falciparum malaria--a case study.
  PLoS One, 4, e7303.  
17334823 K.H.Kim (2007).
Outliers in SAR and QSAR: is unusual binding mode a possible source of outliers?
  J Comput Aided Mol Des, 21, 63-86.  
17875391 P.Gayathri, H.Balaram, and M.R.Murthy (2007).
Structural biology of plasmodial proteins.
  Curr Opin Struct Biol, 17, 744-754.  
17941979 T.Tripathi, S.Rahlfs, K.Becker, and V.Bhakuni (2007).
Glutathione mediated regulation of oligomeric structure and functional activity of Plasmodium falciparum glutathione S-transferase.
  BMC Struct Biol, 7, 67.  
17139078 A.G.Evdokimov, M.Pokross, R.Walter, M.Mekel, B.Cox, C.Li, R.Bechard, F.Genbauffe, R.Andrews, C.Diven, B.Howard, V.Rastogi, J.Gray, M.Maier, and K.G.Peters (2006).
Engineering the catalytic domain of human protein tyrosine phosphatase beta for structure-based drug discovery.
  Acta Crystallogr D Biol Crystallogr, 62, 1435-1445.
PDB codes: 2hc1 2hc2 2i3r 2i3u 2i4e 2i4g 2i4h 2i5x
16699182 D.E.Danley (2006).
Crystallization to obtain protein-ligand complexes for structure-aided drug design.
  Acta Crystallogr D Biol Crystallogr, 62, 569-575.  
16988933 M.Kosloff, G.W.Han, S.S.Krishna, R.Schwarzenbacher, M.Fasnacht, M.A.Elsliger, P.Abdubek, S.Agarwalla, E.Ambing, T.Astakhova, H.L.Axelrod, J.M.Canaves, D.Carlton, H.J.Chiu, T.Clayton, M.DiDonato, L.Duan, J.Feuerhelm, C.Grittini, S.K.Grzechnik, J.Hale, E.Hampton, J.Haugen, L.Jaroszewski, K.K.Jin, H.Johnson, H.E.Klock, M.W.Knuth, E.Koesema, A.Kreusch, P.Kuhn, I.Levin, D.McMullan, M.D.Miller, A.T.Morse, K.Moy, E.Nigoghossian, L.Okach, S.Oommachen, R.Page, J.Paulsen, K.Quijano, R.Reyes, C.L.Rife, E.Sims, G.Spraggon, V.Sridhar, R.C.Stevens, H.van den Bedem, J.Velasquez, A.White, G.Wolf, Q.Xu, K.O.Hodgson, J.Wooley, A.M.Deacon, A.Godzik, S.A.Lesley, and I.A.Wilson (2006).
Comparative structural analysis of a novel glutathioneS-transferase (ATU5508) from Agrobacterium tumefaciens at 2.0 A resolution.
  Proteins, 65, 527-537.
PDB code: 2fno
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.