Structural basis for detoxification and oxidative stress protection in membranes.
Synthesis of mediators of fever, pain and inflammation as well as protection against reactive molecules and oxidative stress is a hallmark of the MAPEG superfamily (membrane associated proteins in eicosanoid and glutathione metabolism). The structure of a MAPEG member, rat microsomal glutathione transferase 1, at 3.2 A resolution, solved here in complex with glutathione by electron crystallography, defines the active site location and a cytosolic domain involved in enzyme activation. The glutathione binding site is found to be different from that of the canonical soluble glutathione transferases. The architecture of the homotrimer supports a catalytic mechanism involving subunit interactions and reveals both cytosolic and membraneous substrate entry sites, providing a rationale for the membrane location of the enzyme.
Holm
Peter J
PJ
Department of Biosciences and Nutrition, Karolinska Institutet and School of Technology and Health, Royal Institute of Technology, SE-14157 Huddinge, Sweden.
Bhakat
Priyaranjan
P
Jegerschöld
Caroline
C
Gyobu
Nobuhiko
N
Mitsuoka
Kaoru
K
Fujiyoshi
Yoshinori
Y
Morgenstern
Ralf
R
Hebert
Hans
H
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D017124:Conserved Sequence; D019281:Dimerization; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism; D008658:Inactivation, Metabolic; D007425:Intracellular Membranes / Q000201:enzymology*; D008051:Lipid Bilayers / Q000737:chemistry*; D008862:Microsomes, Liver / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid
D008051:Lipid Bilayers; D021122:Protein Subunits; C122107:microsomal glutathione S-transferase-I; D005982:Glutathione Transferase; D005978:Glutathione