The three-dimensional map of microsomal glutathione transferase 1 at 6 Å resolution

Abstract

Microsomal glutathione transferase 1 (MGST1) is representative of a superfamily of membrane proteins where different members display distinct or overlapping physiological functions, including detoxication of reactive electrophiles (glutathione transferase), reduction of lipid hydroperoxides (glutathione peroxidase), and production of leukotrienes and prostaglandin E. It follows that members of this superfamily constitute important drug targets regarding asthma, inflammation and the febrile response. Here we propose that this superfamily consists of a new class of membrane proteins built on a common left-handed four-helix bundle motif within the membrane, as determined by electron crystallography of MGST1 at 6 Å resolution. Based on the 3D map and biochemical data we discuss a model for the membrane topology. The 3D structure differs significantly from that of soluble glutathione transferases, which display overlapping substrate specificity with MGST1.