1. Ricciotti, E. & FitzGerald, G. A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol. 31, 986–1000 (2011).

2. Woodward, D. F., Jones, R. L. & Narumiya, S. International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol. Rev. 63, 471–538 (2011).

3. Wang, D. & Dubois, R. N. Eicosanoids and cancer. Nat. Rev. Cancer 10, 181–193 (2010).

4. Michelson, A. D. Antiplatelet therapies for the treatment of cardiovascular disease. Nat. Rev. Drug. Discov. 9, 154–169 (2010).

5. O'Callaghan, G. & Houston, A. Prostaglandin E 2 and the EP receptors in malignancy: possible therapeutic targets? Br. J. Pharmacol. 172, 5239–5250 (2015).

6. Hao, C.-M. & Breyer, M. D. Physiological regulation of prostaglandins in the kidney. Annu. Rev. Physiol. 70, 357–377 (2008).

7. Markovič, T., Jakopin, Ž., Dolenc, M. S. & Mlinarič-Raščan, I. Structural features of subtype-selective EP receptor modulators. Drug Discov. Today 22, 57–71 (2017).

8. Arulkumaran, S. et al. The roles of prostaglandin EP 1 and 3 receptors in the control of human myometrial contractility. J. Clin. Endocrinol. Metab. 97, 489–498 (2012).

9. Kandola, M. K. et al. EP2 receptor activates dual G protein signaling pathways that mediate contrasting proinflammatory and relaxatory responses in term pregnant human myometrium. Endocrinology 155, 605–617 (2014).

10. Potts, M., Prata, N. & Sahin-Hodoglugil, N. N. Maternal mortality: one death every 7 min. Lancet 375, 1762–1763 (2010).

11. Widmer, M. et al. Misoprostol as an adjunct to standard uterotonics for treatment of post-partum haemorrhage: a multicentre, double-blind randomised trial. Lancet 375, 1808–1813 (2010).

12. Allen, R. & O’Brien, B. M. Uses of misoprostol in obstetrics and gynecology. Rev. Obstet. Gynecol. 2, 159–168 (2009).

13. Tsai, B. S., Kessler, L. K., Stolzenbach, J., Schoenhard, G. & Bauer, R. F. Expression of gastric antisecretory and prostaglandin E receptor binding activity of misoprostol by misoprostol free acid. Dig. Dis. Sci. 36, 588–593 (1991).

14. Orobaton, N. et al. Implementing at-scale, community-based distribution of misoprostol tablets to mothers in the third stage of labor for the prevention of postpartum haemorrhage in Sokoto State, Nigeria: early results and lessons learned. PLoS One 12, e0170739 (2017).

15. Xiang, J. et al. Successful strategies to determine high-resolution structures of GPCRs. Trends Pharmacol. Sci. 37, 1055–1069 (2016).

16. Ngo, T. et al. Identifying ligands at orphan GPCRs: current status using structure-based approaches. Br. J. Pharmacol. 173, 2934–2951 (2016).

17. Ballesteros, J. A. & Weinstein, H. in Methods in Neurosciences. Vol. 25 (ed. Sealfon, S.C.) 366–428 (Academic Press, 1995).

18. Schmid, A., Thierauch, K. H., Schleuning, W. D. & Dinter, H. Splice variants of the human EP3 receptor for prostaglandin E2. Eur. J. Biochem. 228, 23–30 (1995).

19. Hua, T. et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature 547, 468–471 (2017).

20. Hua, T. et al. Crystal structure of the human cannabinoid receptor CB1. Cell 167, 750–762.e14 (2016).

21. Audoly, L. & Breyer, R. M. The second extracellular loop of the prostaglandin EP3 receptor is an essential determinant of ligand selectivity. J. Biol. Chem. 272, 13475–13478 (1997).

22. Audoly, L. & Breyer, R. M. Substitution of charged amino acid residues in transmembrane regions 6 and 7 affect ligand binding and signal transduction of the prostaglandin EP3 receptor. Mol. Pharmacol. 51, 61–68 (1997).

23. Ungrin, M. D. et al. Key structural features of prostaglandin E 2 and prostanoid analogs involved in binding and activation of the human EP 1 prostanoid receptor. Mol. Pharmacol. 59, 1446–1456 (2001).

24. Hanson, M. A. et al. Crystal structure of a lipid G protein-coupled receptor. Science 335, 851–855 (2012).

25. Akasaka, H. et al. The key residue within the second extracellular loop of human EP3 involved in selectively turning down PGE 2- and retaining PGE 1- mediated signaling in live cells. Arch. Biochem. Biophys. 616, 20–29 (2017).

26. Abramovitz, M. et al. The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim. Biophys. Acta 1483, 285–293 (2000).

27. Kiriyama, M. et al. Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. Br. J. Pharmacol. 122, 217–224 (1997).

28. Negishi, M. et al. TEI-3356, a highly selective agonist for the prostaglandin EP3 receptor. Prostaglandins 48, 275–283 (1994).

29. Srivastava, A. et al. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513, 124–127 (2014).

30. Negishi, M. et al. Functional interaction of prostaglandin E receptor EP3 subtype with guanine nucleotide-binding proteins, showing low-affinity ligand binding. Biochim. Biophys. Acta 1175, 343–350 (1993).

31. Hamon, M. et al. Modulation of human myometrial PGE 2 receptor by GTP characterization of receptor subtype. Prostaglandins 46, 251–268 (1993).

32. Tsai, B. S., Kessler, L. K., Schoenhard, G., Collins, P. W. & Bauer, R. F. Demonstration of specific E-type prostaglandin receptors using enriched preparations of canine parietal cells and [3H]misoprostol free acid. Am. J. Med. 83, 9–14 (1987).

33. Liang, Y. L. et al. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature 555, 121–125 (2018).

34. Goupil, E. et al. A novel biased allosteric compound inhibitor of parturition selectively impedes the prostaglandin F2alpha-mediated Rho/ROCK signaling pathway. J. Biol. Chem. 285, 25624–25636 (2010).

35. Popov, P. et al. Computational design of thermostabilizing point mutations for G protein-coupled receptors. eLife 7, e34729 (2018).

36. Caffrey, M. & Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nat. Protoc. 4, 706–731 (2009).

37. Liu, W., Ishchenko, A. & Cherezov, V. Preparation of microcrystals in lipidic cubic phase for serial femtosecond crystallography. Nat. Protoc. 9, 2123–2134 (2014).

38. Weierstall, U. et al. Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography. Nat. Commun. 5, 3309 (2014).

39. Barty, A. et al. Cheetah: software for high-throughput reduction and analysis of serial femtosecond X-ray diffraction data. J. Appl. Crystallogr. 47, 1118–1131 (2014).

40. White, T. A. et al. CrystFEL: a software suite for snapshot serial crystallography. J. Appl. Crystallogr. 45, 335–341 (2012).

41. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

42. Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D. Biol. Crystallogr. 68, 352–367 (2012).

43. Smart, O. S. et al. Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER. Acta Crystallogr. D. Biol. Crystallogr. 68, 368–380 (2012).

44. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. Biol. Crystallogr. 66, 486–501 (2010).

45. Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D. Biol. Crystallogr. 66, 12–21 (2010).

46. Sawaya, M. R. et al. Protein crystal structure obtained at 2.9 Å resolution from injecting bacterial cells into an X-ray free-electron laser beam. Proc. Natl. Acad. Sci. USA 111, 12769–12774 (2014).

47. Lomize, M. A., Pogozheva, I. D., Joo, H., Mosberg, H. I. & Lomize, A. L. OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 40, D370–D376 (2012).

48. PyMOL: The PyMOL Molecular Graphics System, Version 2.0 (Schrödinger, LLC., 2015).