7cx3
Cryo-EM structure of the Taprenepag-bound EP2-Gs complexCryo-EM structure of the Taprenepag-bound EP2-Gs complex
Structural highlights
FunctionPE2R2_HUMAN Receptor for prostaglandin E2 (PGE2). The activity of this receptor is mediated by G(s) proteins that stimulate adenylate cyclase. The subsequent raise in intracellular cAMP is responsible for the relaxing effect of this receptor on smooth muscle. Publication Abstract from PubMedSelective modulation of the heterotrimeric G protein alpha S subunit-coupled prostaglandin E(2) (PGE(2)) 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-G(s) complex with its endogenous agonist PGE(2) 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 W(6.48) "toggle switch" and coupling to G(s) 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 PGE(2) signaling system. Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E(2) receptor EP2 subtype.,Qu C, Mao C, Xiao P, Shen Q, Zhong YN, Yang F, Shen DD, Tao X, Zhang H, Yan X, Zhao RJ, He J, Guan Y, Zhang C, Hou G, Zhang PJ, Hou G, Li Z, Yu X, Chai RJ, Guan YF, Sun JP, Zhang Y Sci Adv. 2021 Apr 2;7(14):eabf1268. doi: 10.1126/sciadv.abf1268. Print 2021 Apr. PMID:33811074[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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