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Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions

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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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Acknowledgements

We thank the scientists at Karolinska Institutet (Dr. H. Hebert, Dr. P.-J. Jakobsson and Dr. R. Morgenstern) for the structural information of mGST-1. The scientists at Schrödinger are acknowledged for their technical supports. The authors are also grateful to Dr. T. Benson for his suggestions on the manuscript.

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Authors and Affiliations

  1. Department of Structural and Computational Chemistry, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO, 63017, USA

    Li Xing, Ravi G. Kurumbail, Nicole Caspers & Joseph J. McDonald

  2. Department of Discovery Biology, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO, 63017, USA

    Ronald B. Frazier, Michael S. Davies, Hideji Fujiwara, Robin A. Weinberg, James K. Gierse & William M. Moore

  3. Department of Medicinal Chemistry, St. Louis Laboratories, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO, 63017, USA

    Jeffrey S. Carter & Michael L. Vazquez

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  1. Li Xing
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Correspondence to Li Xing.

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Xing, L., Kurumbail, R.G., Frazier, R.B. et al. Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions. J Comput Aided Mol Des 23, 13–24 (2009). https://doi.org/10.1007/s10822-008-9233-4

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  • DOI: https://doi.org/10.1007/s10822-008-9233-4

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