Characterization of the electrophile binding site and substrate binding mode of the 26-kDa glutathione S-transferase from Schistosoma japonicum

被引:48
作者
Cardoso, RMF
Daniels, DS
Bruns, CM
Tainer, JA
机构
[1] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
[2] Univ Sao Paulo, Inst Fis & Quim Sao Carlos, Grp Cristalog Prot, Sao Carlos, SP, Brazil
[3] Incyte Genom, Palo Alto, CA USA
关键词
glutathione S-transferase; Schistosoma japonicum; lipid peroxidation; 4-hydroxynon-enal; ethacrynic acid; docking; schistosomiasis;
D O I
10.1002/prot.10345
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 beta1-alpha1 loop (Tyr7, Trp8, Ile10, Gly12, Leu13), helix alpha4 (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. Proteins 2003;51:137-146. (C) 2003 Wiley-Liss, Inc.
引用
收藏
页码:137 / 146
页数:10
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