Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics

Abstract

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.

A dynamic Asp–Arg interaction is essential for catalysis in microsomal prostaglandin E 2 synthase

“…In comparison, the much smaller networks found in PDB ID code 4AL1, with a bisphenyl-GSH analog and detergent molecule bound in the active site, indicate that ligand binding can influence network signaling. This finding is also supported by our analysis of recently published inhibitor complexes (15).…”

“…Furthermore, Arg-126 and Asp-49 participate in a charge interaction that could also contribute to catalysis. This structural information is supported by a mesophase crystal structure of an engineered version of mPGES-1 (14) and several inhibitor complexes that have recently been published (15).…”

“…We found that Ser-127 is nonessential for catalysis, whereas Arg-126 and Asp-49 are crucial and mutually dependent for native isomerase activity of the enzyme. Because the latter codependence of activity could be rationalized by a dynamic functional role of these residues, we turned to the highresolution X-ray data (13,15) deposited in the Protein Data Bank (PDB; www.rcsb.org) (16) to provide evidence of their dynamic motion within the crystal structure. Several recent studies have shown that the information present in such data is often underestimated and that it is possible to refine multiple conformations of residues simultaneously, each with individually refined occupancy and B factors, without overfitting the data (17)(18)(19)(20)(21)(22).…”

Lichens as a source of chemical compounds with anti-inflammatory activity

“…Determining the impact of lichen substances on microsomal prostaglandin E2-1 synthase (mPGES-1) was the aim of the subsequent experiments. The purpose of this enzyme is to catalyze the conversion of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2); the mechanism of the inhibition of the enzyme activity was proposed as a strategy for treatment of pain, inflammation, and certain cancers [12]. …”

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…The rigid structure of mPGES-1 with interhelix hydrogen bonds might prevent the required comprehensive conformational changes [31]. Crystal structures of mPGES-1 in complex with an inhibitor were not available until recently, when mPGES-1 was cocrystalized with the high-affinity ligands BI1 and BI2 [38], a 2,4-biarylimidazole, the phenanthrene imidazole MF-63, a MK-886 analogue and an indole-2-carboxylic acid [39].…”