title: Crystal structure of microsomal prostaglandin E2 synthase provides insight into diversity in the MAPEG superfamily.
abstract: Prostaglandin E2 (PGE2) is a key mediator in inflammatory response. The main source of inducible PGE2, microsomal PGE2 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 Å 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-Å-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.
authors: Discovery Sciences, AstraZeneca R&D Mölndal, S-43183 Mölndal, Sweden. tove.sjogren@astrazeneca.com
authors: Tove
authors: T
authors: Sjögren
authors: Johan
authors: J
authors: Nord
authors: Margareta
authors: M
authors: Ek
authors: Patrik
authors: P
authors: Johansson
authors: Gang
authors: G
authors: Liu
authors: Stefan
authors: S
authors: Geschwindner
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000071876:Prostaglandin-E Synthases; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D005978:Glutathione