X-ray structure of Fasciola hepatica Sigma class glutathione transferase 1 reveals a disulfide bond to support stability in gastro-intestinal environment

Kirsty Line, Michail N. Isupov, E. James LaCourse, David Cutress, Russ Morphew, Peter Brophy, Jennifer A. Littlechild

Research output: Contribution to journalArticlepeer-review

3 Citations (SciVal)
173 Downloads (Pure)

Abstract

Sigma class GST (Prostaglandin D synthase), FhGST-S1, is present in the excretory–secretory products (ES) of the liver fluke parasite Fasciola hepatica as cargo of extracellular vesicles (EVs) released by the parasite. FhGST-S1 has a well characterised role in the modulation of the immune response; a key fluke intercession that allows for establishment and development within their hosts. We have resolved the three-dimensional structure of FhGST-S1 in complex with its co-factor glutathione, in complex with a glutathione-cysteine adduct, and in a glutathione disulfide complex in order to initiate a research pipeline to mechanistically understand how FhGST-S1 functions within the host environment and to rationally design selective inhibitors. The overall fold of FhGST-S1 shows high structural similarity to other Sigma class GSTs. However, a unique interdomain disulfide bond was found in the FhGST-S1 which could stabilise the structure within the host gastro-intestinal environment. The position of the two domains of the protein with respect to each other is seen to be crucial in the formation of the active site cleft of the enzyme. The interdomain disulfide bond raises the possibility of oxidative regulation of the active site of this GST protein
Original languageEnglish
Article number902
JournalScientific Reports
Volume9
Issue number1
Early online date29 Jan 2019
DOIs
Publication statusPublished - 01 Dec 2019

Keywords

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Disulfides/chemistry
  • Fasciola hepatica/enzymology
  • Fascioliasis/parasitology
  • Gastrointestinal Tract/parasitology
  • Glutathione Transferase/chemistry
  • Host-Parasite Interactions
  • Models, Molecular
  • Protein Binding
  • Protein Multimerization
  • Structure-Activity Relationship

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