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. 2005 Sep;14(9):2361-9.
doi: 10.1110/ps.051463905. Epub 2005 Aug 4.

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

Jie Li  1 , Zongxiang Xia, Jianping Ding
Affiliations

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

Jie Li et al. Protein Sci. 2005 Sep.

Abstract

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 kappa class is the least studied one among various classes within the superfamily. We report here the expression, purification, and crystal structure of human kappa class GST (hGSTK), which has been determined by the multiple-isomorphous replacement method and refined to 1.93 A resolution. The overall structure of hGSTK is similar to the recently reported structure of kappa 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 theta class GST, suggesting that the kappa class of GST is more closely related to the theta 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.

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Figures

Figure 1.
Figure 1.
Overall structure of the dimeric hGSTK. Two GSF molecules are shown as red ball-and-stick models. (A) View perpendicular to the twofold NCS axis (thick arrow), showing the butterfly-like shape of the dimer. The α-helices and β-sheets are shown in green and in blue, respectively. (B) View showing the binding cleft of the H-site. Domains I and II are shown in green and in blue, respectively. These diagrams were prepared using the program SETOR (Evans 1993).
Figure 2.
Figure 2.
Structure of the catalytic active G-site. (A) SIGMAA-weighted 2Fo–Fc electron density map (1σ contour level) at the G-site. This diagram was prepared using the program TURBO-FRODO. (B) Hydrogen- bonding interactions of the sulfino group of GSF with Ser16 of hGSTK (left), compared with those of the thiol group of GSH with Ser16 of rGSTK (right). Two water molecules bound to the sulfino group of GSF in hGSTK structure are shown as spheres. Hydrogen bonds are shown as dotted lines. This diagram was prepared using the program SETOR.
Figure 3.
Figure 3.
Comparison of the TRX-like domain of hGSTK with other GSTs. (A) Sequence alignment of the TRX-like domains between hGSTK and the representatives of other classes of GSTs. The GSTs used in comparison are human θ GST (PDB entry code 1LJR), human α GST (1K3L), human μ GST (1HNA), human π GST (5GSS), and squid sigma GST (1GSQ). The residue numbers of hGSTK are shown on top. Residues strictly conserved in all classes are shown in red, and the residues identical to and conserved with those of hGSTK in blue and orange, respectively. (B) The Cα atom superposition of the TRX-like domains of hGSTK (Arg6–Ser42 and Pro184–Gly211 in green) and human θ class GST (Leu3–Val33 and Pro55–Gln79 in pink). This diagram was prepared using the program SETOR.
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