4AL0

Crystal Structure of Microsomal Prostaglandin E2 Synthase Provides Insight Into Diversity in the Mapeg Superfamily.

(2013) Proc Natl Acad Sci U S A 110: 3806

• PubMed: 23431194 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1073/pnas.1218504110
• Primary Citation of Related Structures:  
  4AL0, 4AL1


• PubMed 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.

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Organizational Affiliation: 

Discovery Sciences, AstraZeneca R&D Mölndal, S-43183 Mölndal, Sweden. [email protected]