Wucherria bancrofti glutathione S-Transferase: Insights into the 2.3 Å resolution X-ray structure and function, a therapeutic target for human lymphatic filariasis
The notoriety of parasitic nematode survival is directly related to chronic pathogenicity, which is evident in human lymphatic filariasis. It is a disease of poverty which causes severe disability affecting more than 120 million people worldwide. These nematodes down-regulate host immune system thro...
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| Published in: | Biochemical and biophysical research communications Vol. 505; no. 4; pp. 979 - 984 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Elsevier Inc
10-11-2018
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | The notoriety of parasitic nematode survival is directly related to chronic pathogenicity, which is evident in human lymphatic filariasis. It is a disease of poverty which causes severe disability affecting more than 120 million people worldwide. These nematodes down-regulate host immune system through a myriad of strategies that includes secretion of antioxidant and detoxification enzymes like glutathione-S-transferases (GSTs). Earlier studies have shown Wuchereria bancrofti GST to be a potential therapeutic target. Parasite GSTs catalyse the conjugation of glutathione to xenobiotic and other endogenous electrophiles and are essential for their long-term survival in lymph tissues. Hence, the crystal structure of WbGST along with its cofactor GSH at 2.3 Å resolution was determined. Structural comparisons against host GST reveal distinct differences in the substrate binding sites. The parasite xenobiotic binding site is more substrate/solvent accessible. The structure also suggests the presence of putative non-catalytic binding sites that may permit sequestration of endogenous and exogenous ligands. The structure of WbGST also provides a case for the role of the π-cation interaction in stabilizing catalytic Tyr compared to stabilization interactions described for other GSTs. Hence, the obtained information regarding crucial differences in the active sites will support future design of parasite specific inhibitors. Further, the study also evaluates the inhibition of WbGST and its variants by antifilarial diethylcarbamazine through kinetic assays.
•Crystal structure of W. bancrofti GST with its cofactor GSH at 2.3 Å resolution was determined.•Structural comparison against human GST reveals distinct differences in substrate binding sites.•GST xenobiotic binding site is more substrate accessible and reveals non-catalytic binding sites.•Enzyme kinetic assays reveal that antifilarial drug Diethyl carbamazine binds in an uncompetitive manner.•Structural features provide insights to support future design of parasite specific inhibitors. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 0006-291X 1090-2104 |
| DOI: | 10.1016/j.bbrc.2018.09.077 |