PDBsum entry 1pa3

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Transferase PDB id
Protein chains
196 a.a. *
Waters ×32
* Residue conservation analysis

References listed in PDB file
Key reference
Title Native and inhibited structure of a mu class-Related glutathione s-Transferase from plasmodium falciparum.
Authors M.Perbandt, C.Burmeister, R.D.Walter, C.Betzel, E.Liebau.
Ref. J Biol Chem, 2004, 279, 1336-1342. [DOI no: 10.1074/jbc.M309663200]
PubMed id 12972411
The parasite Plasmodium falciparum causes malaria tropica, the most prevailing parasitic disease worldwide, with 300-500 million infections and 1.5-2.7 million deaths/year. The emergence of strains resistant to drugs used for prophylaxis and treatment and no vaccine available makes the structural analysis of potential drug targets essential. For that reason, we analyzed the three-dimensional structure of the glutathione S-transferase from P. falciparum (Pf-GST1) in the apoform and in complex with its inhibitor S-hexyl-glutathione. The structures have been analyzed to 2.6 and 2.2 A, respectively. Pf-GST1 shares several structural features with the Mu-type GSTs and is therefore closely related to this class, even though alignments with its members display low sequence identities in the range of 20-33%. Upon S-hexyl-glutathione binding, the overall structure and the glutathione-binding site (G-site) remain almost unchanged with the exception of the flexible C terminus. The detailed comparison of the parasitic enzyme with the human host Mu-class enzyme reveals that, although the overall structure is homologue, the shape of the hydrophobic binding pocket (H-site) differs substantially. In the human enzyme, it is shielded from one side by the large Mu-loop, whereas in Pf-GST1 the Mu-loop is truncated and the space to recognize and bind voluminous substrates is extended. This structural feature can be exploited to support the design of specific and parasite-selective inhibitors.
Figure 3.
FIG. 3. Stereoview of a ball and stick presentation showing the binding of S-hexyl-GSH at the G-site of Pf-GST1. Carbon atoms are colored in gray, nitrogen atoms are in blue, oxygen atoms are in red, and the sulfur of the inhibitor is shown in yellow. Hydrogen-bonding interactions are indicated in dotted green lines. S-hexyl-GSH is highlighted in yellow. The figure was produced by MOLSCRIPT (41).
Figure 5.
FIG. 5. Surface presentation of the G-site, H-site, and the Mu-loop. a, GST1 from P. falciparum with bound S-hexyl-GSH shown as sticks. There are no interactions between the Mu-loop shown in blue and the C-terminal region shown in yellow. b, the corresponding region of the human Mu-class enzyme GST M2-2 (Protein Data Bank code 1HNA [PDB] ) in complex with glutathione-dinitrobenzene (only the GSH portion of the ligand is shown because of a lack of electron density reported previously (36). The Mu-loop and the C-terminal region are connected by distinct molecular interactions, shielding the G- and H-sites against the solvent. The program GRASP (42) was used to produce the figure.
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 1336-1342) copyright 2004.
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