Structure of proteins and complexes involved in inflammation
The completion of our atomic model of microsomal glutathione transferase 1, MGST1, was an important milestone in the membrane associated proteins in eicosanoid and glutathione metabolism, MAPEG, field since it was the first structure determined from this superfamily of proteins. From the structure we could identify the role of specific amino acid residues for stabilizing the protein and the active site.
A more recently completed electron crystallographic analysis of Microsomal Prostaglandin E synthase 1, MPGES1, resulted in an atomic model. MPGES1 is the inducible enzyme catalyzing the final step to the production of prostaglandin E2 (PGE2) from arachidonic acid. It is a putative drug target for treatment of pain, fever, inflammation and cancer. It is now possible to design experiments to challenge understanding structure – function relationships.
We are fortunate to have access to inhibitors of MPGES1 through close collaboration with a biotech company screening for drug candidates. By using some of these we observed a difference in behavior between rat and human MPGES1 in spite of minor sequence differences. This has now been explored by creating rat/human chimera as well as point mutations based on the atomic model demonstrating importance of specific residues for activity. By doing appropriate changes it is for example possible to humanize the rat enzyme and vice versa.
Current work is focused on structural refinements, co-crystallization with ligands and inhibitors, and studies of protein complexes (see also the nanodisc project below).