Structure of the major cytosolic glutathione S-transferase from the parasitic nematode Onchocerca volvulus.
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| Abstract |
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.
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| Authors | Markus Perbandt, Jana Höppner, Christian Betzel, Rolf D Walter, Eva Liebau |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 13 Pg. 12630-6 (Apr 01 2005) ISSN: 0021-9258 [Print] United States |
| PMID | 15640152 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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