No abstract

Selective modulation of the heterotrimeric G protein α S subunit–coupled prostaglandin E2 (PGE2) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo–electron microscopy structure of the EP2-Gs complex with its endogenous agonist PGE2 and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W6.48 “toggle switch” and coupling to Gs via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE2 signaling system.

Three series of POSS containing organic-inorganic molecular hybrid low dielectric materials with different molecular architectures were prepared, in which isobutylstyryl-polyhedral oligomeric silsesquioxane (IBS-POSS) and octavinyl-polyhedral oligomeric silsesquioxane (OV-POSS) were adopted as an inorganic core to construct the pendant-type PAS-POSS pendt and star-type PAS-POSS star hybrids, respectively. Among the organic-inorganic molecular hybrids, the POSS contents range from 0.65, 1.36, 1.62, to 3.14 in molar percentage (mol %) in PAS-POSS pendt hybrids, and from 0.36, 1.37, 2.06, to 3.72 in molar percentage (mol %) in PAS-POSS star hybrids. Different polar organic components (organic polymeric chains) including PS, PAS, and PMMA were build into the star-type hybrids. The analysis on the relationship between molecular structure of these hybrids and their dielectric constants indicates that the incorporation of POSS molecules into the polymer matrixes will lower the dielectric constant (k) of the resulted hybrids (both pendant-type and star-type). At the same POSS content, the star-type hybrids possess a lower k than those of pendant-type ones, which is mainly assigned to the larger free volume resulted from star-type hybrids. Simultaneously, it is found that the dielectric constant of the resulting hybrids increases with the polarity of organic polymeric chain when possessing the similar molecular structure and POSS content.