The glutathione-dependent enzyme microsomal prostaglandin E synthase-1 (MPGES1) plays a pivotal role in inflammatory diseases. MPGES1 is up-regulated by pro-inflammatory cytokines in concert with cyclooxygenase (COX) -2, and the concerted action of both enzymes leads to the production of induced prostaglandin E2 (PGE2), a potent lipid mediator of inflammation, pain, and fever. Non-steroidal anti-inflammatory drugs (NSAIDs) as well as COX-2 specific inhibitors (COXIBs) are widely used analgesics that interfere with PGE2 production by inhibiting COX. However, use of these drugs is often connected with severe side effects such as gastrointestinal bleeding and cardiovascular events, respectively. This is because these drugs impair the levels of lipid mediators whose formation depends on COX but not on MPGES1. Therefore, specific inhibition of MPGES1 is regarded as a promising strategy in the treatment of inflammatory diseases. MPGES1 inhibitors are currently developed, and it is expected that these novel pharmaceuticals display less severe adverse drug effects while potently eliminating the pro-inflammatory effects of induced PGE2. We have conducted studies on the structure and function of MPGES1 in order to understand how this enzyme and its inhibitors work on a molecular level, and the effects of MPGES1 inhibition have been investigated in several disease states. In paper I, the structure of the integral membrane protein MPGES1 was elucidated by electron crystallography. Heterologously expressed human MPGES1 was purified to apparent homogeneity and subjected to two-dimensional crystallisation in the presence of phospholipids. Elastic electron scattering induced by the protein crystals at various angles was used to calculate the three-dimensional structure at 3.5 Å, which was validated by site-directed mutagenesis of structurally and functionally important residues. MPGES1 shows a homotrimeric organisation. Reduced glutathione (GSH), an essential co-factor of MPGES1, binds between two adjacent subunits, but it is ...