Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions |
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Authors: | Li Xing Ravi G Kurumbail Ronald B Frazier Michael S Davies Hideji Fujiwara Robin A Weinberg James K Gierse Nicole Caspers Jeffrey S Carter Joseph J McDonald William M Moore Michael L Vazquez |
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Institution: | (1) Department of Structural and Computational Chemistry, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA;(2) Department of Discovery Biology, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA;(3) Department of Medicinal Chemistry, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA |
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Abstract: | Inducible, microsomal prostaglandin E synthase 1 (mPGES-1), the terminal enzyme in the prostaglandin (PG) biosynthetic pathway,
constitutes a promising therapeutic target for the development of new anti-inflammatory drugs. To elucidate structure–function
relationships and to enable structure-based design, an mPGES-1 homology model was developed using the three-dimensional structure
of the closest homologue of the MAPEG family (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism), mGST-1.
The ensuing model of mPGES-1 is a homo-trimer, with each monomer consisting of four membrane-spanning segments. Extensive
structure refinement revealed an inter-monomer salt bridge (K26-E77) as well as inter-helical interactions within each monomer,
including polar hydrogen bonds (e.g. T78-R110-T129) and hydrophobic π-stacking (F82-F103-F106), all contributing to the overall
stability of the homo-trimer of mPGES-1. Catalytic co-factor glutathione (GSH) was docked into the mPGES-1 model by flexible
optimization of both the ligand and the protein conformations, starting from the initial location ascertained from the mGST-1
structure. Possible binding site for the substrate, prostaglandin H2 (PGH2), was identified by systematically probing the refined molecular structure of mPGES-1. A binding model was generated by induced
fit docking of PGH2 in the presence of GSH. The homology model prescribes three potential inhibitor binding sites per mPGES-1 trimer. This was
further confirmed experimentally by equilibrium dialysis study which generated a binding stoichiometric ratio of approximately
three inhibitor molecules to three mPGES-1 monomers. The structural model that we have derived could serve as a useful tool
for structure-guided design of inhibitors for this emergently important therapeutic target. |
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Keywords: | Microsomal prostaglandin E synthase type 1 (mPGES-1) Prostaglandin H2 (PGH2) Glutathione (GSH) Homo-trimer Three-fold symmetry Homology modeling Induced fit docking Binding stoichiometry Structure-based design |
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