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Thioredoxin-like domain of human class glutathione transferase reveals sequence homology and structure similarity to the class enzyme

¹ State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry and ² Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China

(RECEIVED March 16, 2005; FINAL REVISION May 24, 2005; ACCEPTED May 24, 2005)

Glutathione transferases (GSTs) are a superfamily of enzymes that play a vital functional role in the cellular detoxification process. They catalyze the conjugation of the thiol group of glutathione (GSH) to the electrophilic groups of a wide range of hydrophobic substrates, leading to an easier removal of the latter from the cells. The class is the least studied one among various classes within the superfamily. We report here the expression, purification, and crystal structure of human class GST (hGSTK), which has been determined by the multiple-isomorphous replacement method and refined to 1.93 Å resolution. The overall structure of hGSTK is similar to the recently reported structure of class GST from rat mitochondrion. Each subunit of the dimeric hGSTK contains a thioredoxin (TRX)-like domain and a helical domain. A molecule of glutathione sulfinate, an oxidized product of GSH, is found to bind at the G site of each monomer. One oxygen atom of the sulfino group of GSF forms a hydrogen bond with the hydroxyl group of the catalytic residue Ser16. The TRX-like domain of hGSTK shares 19% sequence identity and structure similarity with human class GST, suggesting that the class of GST is more closely related to the class enzyme within the GST superfamily. The structure of the TRX-like domain of hGSTK is also similar to that of glutathione peroxidase (GPx), implying an evolutionary relationship between GST and GPx.

Keywords: glutathione transferase; crystal structure; active site; glutathione sulfinate; thioredoxin-like domain; glutathione peroxidase

Abbreviations: GST, glutathione transferase • hGSTK, human class GST • rGSTK, rat mitochondrial class GST • GSH, glutathione • GSF, glutathione sulfinate • TRX, thioredoxin • CDNB, 1-chloro-2,4-dinitrobenzene • DTT, dithiothreitol • MIR, multiple-isomorphous replacement • NCS, noncrystallographic symmetry • RMS, root-mean-square • GPx, glutathione peroxidase • PEG, polyethylene glycol.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051463905.

Reprint requests to: Zongxiang Xia, State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P.R. China; e-mail: xiazx{at}mail.sioc.ac.cn; fax: +86-21-64166128; or Jianping Ding, Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, P.R. China; e-mail: jpding{at}sibs.ac.cn; fax: +86-21-54921116.

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