The three-dimensional map of microsomal glutathione transferase 1 at 6 A 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 A 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.

Structural Basis for Detoxification and Oxidative Stress Protection in Membranes

“…We have now solved the structure of the rat enzyme to 3.2 Å in plane resolution (4.0 Å perpendicular to the membrane plane) using data from both crystal forms ( Figure 1(a) and Table 1). As previously described 7,8 both the p6 and the p22 1 2 1 maps contain densities with three repeats of left-handed four-helix bundles making up a homotrimer known to be the functional unit 3,9 (Figure 1(b), (c) and (d)). To evaluate the degree of non-crystallographic symmetry in the p22 1 2 1 crystal form, monomers from the unsymmetrised map were correlated.…”

Human Microsomal Prostaglandin E Synthase-1

“…In the case of MGST1 two different types of two-dimensional crystals have been observed. The hexagonal form has a perfect 3-fold axis relating the three monomers in the trimer (54,55), whereas the orthorhombic type has a local non-crystallographic 3-fold axis (56). The high degree of 3-fold symmetry between the monomers displayed by that protein is less pronounced in the present projection map of mPGES-1.…”

Reactive Intermediates and The Dynamics of Glutathione Transferases

“…This observation, together with subsequent work, has firmly established the concept that microsomal glutathione transferase 1 (MGST1) activation occurs with a large variety of electrophiles (of which some are reactive intermediates). During the last 20 years, MGST1 has been extensively studied regarding gene structure (Kelner et al, 1996(Kelner et al, , 2000Iida et al, 2001), organ and species distribution (Estonius et al, 1999), molecular properties (Morgenstern et al, 1982(Morgenstern et al, , 1988Weinander et al, 1997;Svensson et al, 2000), three-dimensional structure (Schmidt-Krey et al, 2000), regulation (Andersson et al, 1994), and mechanism (Morgenstern et al, 2001). Recently, MGST1 has been grouped in a new superfamily named membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) (Jakobsson et al, 1999a), which is involved not only in xenobiotic metabolism and cellular protection but potentially also in pain, fever, inflammation, cancer, apoptosis, allergy, and asthma (Jakobsson et al, 1999b;Funk, 2001).…”