Structure of the major cytosolic glutathione S-transferase from the parasitic nematode Onchocerca volvulus.
Onchocerciasis is a debilitating parasitic disease caused by the filarial worm Onchocerca volvulus. Similar to other helminth parasites, O. volvulus is capable of evading the host's immune responses by a variety of defense mechanisms, including the detoxification activities of the glutathione S-transferases (GSTs). Additionally, in response to drug treatment, helminth GSTs are highly up-regulated, making them tempting targets both for chemotherapy and for vaccine development. We analyzed the three-dimensional x-ray structure of the major cytosolic GST from O. volvulus (Ov-GST2) in complex with its natural substrate glutathione and its competitive inhibitor S-hexylglutathione at 1.5 and 1.8 angstrom resolution, respectively. From the perspective of the biochemical classification, the Ov-GST2 seems to be related to pi-class GSTs. However, in comparison to other pi-class GSTs, in particular to the host's counterpart, the Ov-GST2 reveals significant and unusual differences in the sequence and overall structure. Major differences can be found in helix alpha-2, an important region for substrate recognition. Moreover, the binding site for the electrophilic co-substrate is spatially increased and more solvent-accessible. These structural alterations are responsible for different substrate specificities and will form the basis of parasite-specific structure-based drug design investigations.
Perbandt
Markus
M
Institute of Biochemistry and Foodchemistry, Department of Biochemistry and Molecularbiology, University of Hamburg, Martin Luther King Platz 6, 20146 Hamburg, Germany. Perbandt@chemie.uni-hamburg.de
Höppner
Jana
J
Betzel
Christian
C
Walter
Rolf D
RD
Liebau
Eva
E
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000201:enzymology* / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017181:Onchocerca volvulus / Q000201:enzymology* / Q000378:metabolism; D010920:Placenta / Q000201:enzymology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015854:Up-Regulation
D005982:Glutathione Transferase; D005978:Glutathione; C033550:hexylglutathione