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Publication Abstract from PubMed

Prostaglandin E (PGE) is a key mediator in inflammatory response. The main source of inducible PGE, microsomal PGE synthase-1 (mPGES-1), has emerged as an interesting drug target for treatment of pain. To support inhibitor design, we have determined the crystal structure of human mPGES-1 to 1.2 A resolution. The structure reveals three well-defined active site cavities within the membrane-spanning region in each monomer interface of the trimeric structure. An important determinant of the active site cavity is a small cytosolic domain inserted between transmembrane helices I and II. This extra domain is not observed in other structures of proteins within the MAPEG (Membrane-Associated Proteins involved in Eicosanoid and Glutathione metabolism) superfamily but is likely to be present also in microsomal GST-1 based on sequence similarity. An unexpected feature of the structure is a 16-A-deep cone-shaped cavity extending from the cytosolic side into the membrane-spanning region. We suggest a potential role for this cavity in substrate access. Based on the structure of the active site, we propose a catalytic mechanism in which serine 127 plays a key role. We have also determined the structure of mPGES-1 in complex with a glutathione-based analog, providing insight into mPGES-1 flexibility and potential for structure-based drug design.

Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily.,Sjogren T, Nord J, Ek M, Johansson P, Liu G, Geschwindner S Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3806-11. doi:, 10.1073/pnas.1218504110. Epub 2013 Feb 19. PMID:23431194^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.