Glutathione reductase, domain structures

FIGURE 6.34 Sheet structures formed from andparallel arrangements of /3-strands, (a) Streptomyces suh i x Xu inhibitor, (b) glutathione reductase domain 3, and (c) the second domain of glyceraldehyde-3-phosphate dehydrogenase represent minimal andparallel /S-sheet domain structures. In each of these cases, an andparallel /S-sheet is largely exposed to solvent on one face and covered by helices and random coils on the other face. (Jane Richardson)... 

Fig. 105. Examples of small disulfide-rich or metal-rich proteins (shown on the right side) compared with their more regular counterparts in other structural categories (shown at the left), (a) Tobacco mosaic virus protein, an up-and-down helix bundle (b) cytochrome bs, a distorted up-and-down helix bundle (c) trypsin domain 1, a Greek key antiparallel /3 barrel (d) high-potential iron protein, a distorted Greek key /3 barrel (e) glutathione reductase domain 3, an open-face sandwich fi sheet (f) ferredoxin, a distorted open-face sandwich f) sheet.

Figure 15-10 The three-dimensional structure of glutathione reductase. Bound FAD is shown. NAD+ binds to a separate domain below the FAD. The two cysteine residues forming the reducible disulfide loop are indicated by dots. From Thieme et al.182...

There are five classes of flavin-binding structural folds presented in Table 1 that are identified by the prototype protein in which they were first discovered. These are flavodoxin (FDX), ferredoxin reductase (FNR), triosephosphate isomerase (TIM), glutathione reductase (GR) and p-cresol methylhydroxylase (PCMH). The topologies of four of these five domains are shown in Figure 2. There are also four classes of primary acceptor/donor domain folds that are identified by the prototype protein where they were first discovered. They are cytochrome P450BMP (BMP), cytochrome b5 (CYTB5), cytochrome c (CYTC) and the 2Fe-2S plant-type ferredoxin (FDN). 

FIGURE 3. Ca trace illustrating the structural similarity between the small domain of TMADH (solid line) and the NADPH-binding domain of glutathione reductase (dashed line). 

Taschner and coworkers proposed a similar model based on two other fla-voenzymes the human and E. coli glutathione reductase. The FAD binding domain of glutathione reductase and p-hydroxybenzoate hydroxylase have been shown to resemble each other closely via comparison of their respective X-ray crystal structures. Extrapolating this information to CHMO leads to the proposal that the hydroperoxide is attached to the re-face of the isoalloxazine ring and that the ketone substrates approach the hydroperoxide from the direction of the dimethylbenzene moiety[97). Further stereochemical and stereoelectronic considerations lead to a hypothesis explaining the observed stereoselectivities. 

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