6rwd
Crystal structure of SjGST in complex with GSH and ellagic acid at 1.53 Angstrom resolution
Structural highlights
FunctionGST26_SCHJA Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. GST isoenzymes appear to play a central role in the parasite detoxification system. Other functions are also suspected including a role in increasing the solubility of haematin in the parasite gut. Publication Abstract from PubMedSchistosoma japonicum glutathione transferase (Sj26GST), an enzyme central to detoxification of electrophilic compounds in the parasite, is upregulated in response to drug treatment. Therefore, Sj26GST may serve as a potential therapeutic target for the treatment of schistosomiasis. Herewith, we describe the structural basis of inhibition of Sj26GST by ellagic acid (EA). Using 1-chloro-2,4-dinitrobenzene and reduced glutathione (GSH) as Sj26GST substrates, EA was shown to inhibit Sj26GST activity by 66 % with an IC50 of 2.4 muM. Fluorescence spectroscopy showed that EA altered the polarity of the environment of intrinsic tryptophan and that EA decreased (in a dose-dependent manner) the interaction between Sj26GST and 8-Anilino-1-naphthalenesulfonate (ANS), which is a known GST H-site ligand. Thermodynamic studies indicated that the interaction between Sj26GST and EA is spontaneous (DeltaG = -29.88 +/- 0.07 kJ/mol), enthalpically-driven (DeltaH = -9.48 +/- 0.42 kJ/mol) with a favourable entropic change (DeltaS = 20.40 +/- 0.08 kJ/mol/K), and with a stoichiometry of four EA molecules bound per Sj26GST dimer. The 1.53 A-resolution Sj26GST crystal structure (P 21 21 21 space group) complexed with GSH and EA shows that EA binds primarily at the dimer interface, stabilised largely by Van der Waal forces and H-bonding. Besides, EA bound near the H-site and less than 3.5 A from the epsilon-NH2 of the gamma-glutamyl moiety of GSH, in each subunit. Molecular basis of inhibition of Schistosoma japonicum glutathione transferase by ellagic acid: Insights into biophysical and structural studies.,Akumadu BO, Pandian R, Olfsen J, Worth R, Thulo M, Mentor T, Fanucchi S, Sayed Y, Dirr HW, Achilonu I Mol Biochem Parasitol. 2020 Sep 19;240:111319. doi:, 10.1016/j.molbiopara.2020.111319. PMID:32961204[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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