Title

Characterization of the Electrophile Binding Site and Substrate Binding Mode of the 26-kDa Glutathione S-transferase from Schistosoma japonicum

Document Type

Article

Publication Date

2003

Publication Source

Proteins

Abstract

The 26‐kDa glutathione S‐transferase from Schistosoma japonicum (Sj26GST), a helminth worm that causes schistosomiasis, catalyzes the conjugation of glutathione with toxic secondary products of membrane lipid peroxidation. Crystal structures of Sj26GST in complex with glutathione sulfonate (Sj26GSTSLF), S‐hexyl glutathione (Sj26GSTHEX), and S‐2‐iodobenzyl glutathione (Sj26GSTIBZ) allow characterization of the electrophile binding site (H site) of Sj26GST. The S‐hexyl and S‐2‐iodobenzyl moieties of these product analogs bind in a pocket defined by side‐chains from the β1‐α1 loop (Tyr7, Trp8, Ile10, Gly12, Leu13), helix α4 (Arg103, Tyr104, Ser107, Tyr111), and the C‐terminal coil (Gln204, Gly205, Trp206, Gln207). Changes in the Ser107 and Gln204 dihedral angles make the H site more hydrophobic in the Sj26GSTHEX complex relative to the ligand‐free structure. These structures, together with docking studies, indicate a possible binding mode of Sj26GST to its physiologic substrates 4‐hydroxynon‐2‐enal (4HNE), trans‐non‐2‐enal (NE), and ethacrynic acid (EA). In this binding mode, hydrogen bonds of Tyr111 and Gln207 to the carbonyl oxygen atoms of 4HNE, NE, and EA could orient the substrates and enhance their electrophilicity to promote conjugation with glutathione.

Inclusive pages

137–146.

ISBN/ISSN

0887-3585

Publisher

John Wiley & Sons

Volume

51

Peer Reviewed

yes

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