title: Structural analysis of human alpha-class glutathione transferase A1-1 in the apo-form and in complexes with ethacrynic acid and its glutathione conjugate.
abstract: BACKGROUND
  Glutathione transferases (GSTs) constitute a family of isoenzymes that catalyze the conjugation of the tripeptide glutathione with a wide variety of hydrophobic compounds bearing an electrophilic functional group. Recently, a number of X-ray structures have been reported which have defined both the glutathione- and the substrate-binding sites in these enzymes. The structure of the glutathione-free enzyme from a mammalian source has not, however, been reported previously.
  
  
  RESULTS
  We have solved structures of a human alpha-class GST, isoenzyme A1-1, both in the unliganded form and in complexes with the inhibitor ethacrynic acid and its glutathione conjugate. These structures have been refined to resolutions of 2.5 A, 2.7 A and 2.0 A respectively. Both forms of the inhibitor are clearly present in the associated electron density.
  
  
  CONCLUSIONS
  The major differences among the three structures reported here involve the C-terminal alpha-helix, which is a characteristic of the alpha-class enzyme. This helix forms a lid over the active site when the hydrophobic substrate binding site (H-site) is occupied but it is otherwise disordered. Ethacrynic acid appears to bind in a non-productive mode in the absence of the coenzyme glutathione.
authors.affiliation: Department of Molecular Biology, Uppsala University, Sweden.
authors.forename: A D
authors.initials: AD
authors.lastname: Cameron
authors.forename: I
authors.initials: I
authors.lastname: Sinning
authors.forename: G
authors.initials: G
authors.lastname: L'Hermite
authors.forename: B
authors.initials: B
authors.lastname: Olin
authors.forename: P G
authors.initials: PG
authors.lastname: Board
authors.forename: B
authors.initials: B
authors.lastname: Mannervik
authors.forename: T A
authors.initials: TA
authors.lastname: Jones
mesh_terms: D001051:Apoenzymes / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray / Q000379:methods; D004976:Ethacrynic Acid / Q000031:analogs & derivatives / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism*; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D046911:Macromolecular Substances; D008958:Models, Molecular; D017433:Protein Structure, Secondary
chemical_list: D001051:Apoenzymes; D007527:Isoenzymes; D046911:Macromolecular Substances; D005982:Glutathione Transferase; D005978:Glutathione; D004976:Ethacrynic Acid