Researchers from Karolinska Institutet and KTH has in co-operation with researchers from Japan determined the structure of the enzyme Microsomalprostaglandin E synthase 1 (MPGES1). MPGES1 has been implicated in a number of human diseases or pathological conditions, such as rheumatoid arthritis,fever, and pain, and is therefore regarded as a primary target for development of novel anti-inflammatory drugs. Prostaglandins (PG) are bioactive lipids produced from arachidonic acid via the action of cyclooxygenases and terminal PG synthases. Microsomal prostaglandin E synthase 1 (MPGES1) constitutes an inducible glutathione-dependent integral membrane protein that catalyses the oxidoreduction of cyclooxygenase derived PGH2 into PGE2. MPGES1 has been implicated in a number of human diseases or pathological conditions, such as rheumatoid arthritis, fever, and pain. To provide a structural basis for insight in the catalytic mechanism, they determined the structure of MPGES1 in complex with glutathione by electron crystallography from 2D crystals induced in the presence of phospholipids. Together with results from site-directed mutagenesis and activity measurements, they could thereby demonstrate the role of specific amino acid residues. Glutathione is found to bind in a U-shaped conformation at the interface between subunits in the protein trimer. It is exposed to a site facing the lipid bilayer, which forms the specific environment for the oxidoreduction of PGH2 to PGE2 after displacement of the cytoplasmic half of the N-terminal transmembrane helix. Hence, insight into the dynamic behaviour of MPGES1 and homologous membrane proteins in inflammation and detoxification is provided.

Karolinska Institutet