Wucherria bancrofti glutathione S-Transferase: Insights into the 2.3 Å resolution X-ray structure and function, a therapeutic target for human lymphatic filariasis
| Autor: | Christian Betzel, Markus Perbandt, Jayaprakasam Madhumathi, Prince R. Prabhu, Sakthi Devi Moorthy, Satya Narayan Pradhan, Perumal Kaliraj |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Biophysics Crystallography X-Ray medicine.disease_cause Biochemistry 03 medical and health sciences chemistry.chemical_compound Elephantiasis Filarial medicine Animals Diethylcarbamazine Humans Wuchereria bancrofti Secretion Binding site Molecular Biology Lymphatic filariasis Glutathione Transferase Binding Sites biology Cell Biology Glutathione medicine.disease Antiparasitic agent Kinetics 030104 developmental biology Glutathione S-transferase chemistry biology.protein Xenobiotic |
| Zdroj: | Biochemical and Biophysical Research Communications. 505:979-984 |
| ISSN: | 0006-291X |
| Popis: | 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 A 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. |
| Databáze: | OpenAIRE |
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