Structure determination and refinement of human alpha class glutathione transferase A1-1, and a comparison with the Mu and Pi class enzymes

The crystal structure of human alpha class glutathione transferase A1-1 has been determined and refined to a resolution of 2.6 Å. There are two copies of the dimeric enzyme in the asymmetric unit. Each monomer is built from two domains. A bound inhibitor, S-benzyl-glutathione, is primarily associated with one of these domains via a network of hydrogen bonds and salt-links. In particular, the sulphur atom of the inhibitor forms a hydrogen bond to the hydroxyl group of Tyr9 and the guanido group of Arg15. The benzyl group of the inhibitor is completely buried in a hydrophobic pocket. The structure shows an overall similarity to the mu and pi class enzymes particularly in the "glutathione-binding domain". The main difference concerns the extended C terminus of the alpha class enzyme which forms an extra α-helix that blocks one entrance to the active site and makes up part of the substrate binding site.