Journal Article

PUBDB-2018-05492

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Wucherria bancrofti glutathione S-Transferase: Insights into the 2.3 Å resolution X-ray structure and function, a therapeutic target for human lymphatic filariasis

Rajaiah Prabhu, P. ; Moorthy, S. D. ; Madhumathi, J. ; Pradhan, S. N. ; Perbandt, M.Extern*EMBL* ; Betzel, C. (Corresponding author)Extern* ; Kaliraj, P. (Corresponding author)

2018
Academic Press Orlando, Fla.

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Please use a persistent id in citations: doi:10.1016/j.bbrc.2018.09.077

Abstract: 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.

Note: © Elsevier Inc.

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Contributing Institute(s):

1. DOOR-User (DOOR)
2. beauftragt von UNI (UNI/CUI)
3. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (POF3-622) (POF3-622)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; ClosedAccess ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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