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Cited by 19Receptor Mechanisms and SignalingProtein Kinase Regulation and GTPase SignalingComputational Drug Discovery Methods

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Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity

Open access
Lv, Xiuqing, Gao, Kaixuan, Nie, Jia, Zhang, Xin, Zhang, Shuhao, Ren, Yinhang, Sun, Xiaoou, Li, Qi, Huang, Jingrui, Liu, Lijuan, Zhang, Xiaowen, Zhang, Weishe, Liu, Xiangyu·2023·Nature Communications
DOI 10.1038/s41467-023-43922-8PMC PMC10709307

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Abstract

Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F 2α and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (EP3 receptor) by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. Here, we present two cryo-EM structures of the FP receptor bound to carboprost and latanoprost-FA (the free acid form of latanoprost) at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs.

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  1. 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). · DOI
  2. Jin, D. & Zhong, T. P. Prostaglandin signaling in ciliogenesis and development. J. Cell. Physiol. 237, 2632–2643 (2022). · DOI
  3. Hirata, T. & Narumiya, S. Prostanoid receptors. Chem. Rev. 111, 6209–6230 (2011). · DOI
  4. Qu, C. et al. Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E(2) receptor EP2 subtype. Sci. Adv. 7, eabf1268 (2021). · DOI
  5. Morimoto, K. et al. Crystal structure of the endogenous agonist-bound prostanoid receptor EP3. Nat. Chem. Biol. 15, 8–10 (2019). · DOI
  6. Nojima, S. et al. Cryo-EM structure of the prostaglandin E receptor EP4 coupled to G protein. Structure 29, 252–260.e256 (2021). · DOI
  7. Wu, C. et al. Ligand-induced activation and G protein coupling of prostaglandin F(2α) receptor. Nat. Commun. 14, 2668 (2023). · DOI
  8. Schlötzer-Schrehardt, U., Zenkel, M. & Nüsing, R. M. Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues. Investig. Ophthalmol. Vis. Sci. 43, 1475–1487 (2002).
  9. Al-Matubsi, H. Y. et al. Expression and localization of the contractile prostaglandin F receptor in pregnant rat myometrium in late gestation, labor, and postpartum. Biol. Reprod. 65, 1029–1037 (2001). · DOI
  10. Abramovitz, M. et al. Cloning and expression of a cDNA for the human prostanoid FP receptor. J. Biol. Chem. 269, 2632–2636 (1994). · DOI
  11. Say, L. et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob. health 2, e323–e333 (2014). · DOI · Paper page
  12. Merriam, A. A. et al. Risk for postpartum hemorrhage, transfusion, and hemorrhage-related morbidity at low, moderate, and high volume hospitals. J. Matern. Fetal Neonatal Med. 31, 1025–1034 (2018). · DOI
  13. Ansari, J. R. et al. Calcium chloride for the prevention of uterine atony during cesarean delivery: a pilot randomized controlled trial and pharmacokinetic study. J. Clin. Anesth. 80, 110796 (2022). · DOI
  14. Senior, J., Marshall, K., Sangha, R. & Clayton, J. K. In vitro characterization of prostanoid receptors on human myometrium at term pregnancy. Br. J. Pharmacol. 108, 501–506 (1993). · DOI
  15. Chen, Y. et al. Prostaglandins for postpartum hemorrhage: pharmacology, application, and current opinion. Pharmacology 106, 477–487 (2021). · DOI
  16. Butwick, A. J. et al. Second-line uterotonics and the risk of hemorrhage-related morbidity. Am. J. Obstet. Gynecol. 212, 642.e641–647 (2015). · DOI
  17. Bygdeman, M. Pharmacokinetics of prostaglandins. Best. Pract. Res. Clin. Obstet. Gynaecol. 17, 707–716 (2003). · DOI
  18. Blomqvist, A. & Engblom, D. Neural mechanisms of inflammation-induced fever. Neuroscientist 24, 381–399 (2018). · DOI
  19. Machado, N. L. S., Bandaru, S. S., Abbott, S. B. G. & Saper, C. B. EP3R-expressing glutamatergic preoptic neurons mediate inflammatory fever. J. Neurosci. 40, 2573–2588 (2020). · DOI
  20. Zeng, R. et al. Prostaglandin F(2α) evokes vasoconstrictor and vasodepressor activities that are both independent of the F prostanoid receptor. FASEB J. 36, e22293 (2022). · DOI
  21. Abramovitz, M. et al. The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim. et. Biophys. Acta 1483, 285–293 (2000). · DOI
  22. Choi, Y. M., Diehl, J. & Levins, P. C. Promising alternative clinical uses of prostaglandin F2alpha analogs: beyond the eyelashes. J. Am. Acad. Dermatol. 72, 712–716 (2015). · DOI
  23. Sjöquist, B. & Stjernschantz, J. Ocular and systemic pharmacokinetics of latanoprost in humans. Surv. Ophthalmol. 47, S6–S12 (2002). · DOI
  24. Harris, J. A. et al. Selective G protein signaling driven by substance P-neurokinin receptor dynamics. Nat. Chem. Biol. 18, 109–115 (2022). · DOI
  25. Nehmé, R. et al. Mini-G proteins: novel tools for studying GPCRs in their active conformation. PLoS One 12, e0175642 (2017). · DOI
  26. Toyoda, Y. et al. Ligand binding to human prostaglandin E receptor EP(4) at the lipid-bilayer interface. Nat. Chem. Biol. 15, 18–26 (2019). · DOI
  27. Audet, M. et al. Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor. Nat. Chem. Biol. 15, 11–17 (2019). · DOI
  28. Ballesteros J. A., Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. In: Methods in Neurosciences (edn Sealfon S. C.) (Academic Press, 1995). · DOI
  29. Flock, T. et al. Universal allosteric mechanism for Gα activation by GPCRs. Nature 524, 173–179 (2015). · DOI
  30. Suno, R. et al. Structural insights into the G protein selectivity revealed by the human EP3-G(i) signaling complex. Cell Rep. 40, 111323 (2022). · DOI
  31. Gregorio, G. G. et al. Single-molecule analysis of ligand efficacy in beta(2)AR-G-protein activation. Nature 547, 68–73 (2017). · DOI
  32. Maeda, S., Qu, Q., Robertson, M. J., Skiniotis, G. & Kobilka, B. K. Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science 364, 552–557 (2019). · DOI
  33. Qian, Y. et al. Structural insights into adhesion GPCR ADGRL3 activation and G(q), G(s), G(i), and G(12) coupling. Mol. Cell 82, 4340–4352.e4346 (2022). · DOI
  34. Narumiya, S., Sugimoto, Y. & Ushikubi, F. Prostanoid receptors: structures, properties, and functions. Physiol. Rev. 79, 1193–1226 (1999). · DOI
  35. Sugimoto, Y., Inazumi, T. & Tsuchiya, S. Roles of prostaglandin receptors in female reproduction. J. Biochem. 157, 73–80 (2015). · DOI
  36. Vallera, C., Choi, L. O., Cha, C. M. & Hong, R. W. Uterotonic medications: oxytocin, methylergonovine, carboprost, misoprostol. Anesthesiol. Clin. 35, 207–219 (2017). · DOI
  37. Escobar, M. F. et al. FIGO recommendations on the management of postpartum hemorrhage 2022. Int. J. Gynaecol. Obstet. 157, 3–50 (2022). · DOI
  38. Tanase, C., Pintilie, L. & Tanase, R. E. Lactones in the synthesis of prostaglandins and prostaglandin analogs. Int. J. Mol. Sci. 22, 1572 (2021). · DOI
  39. Zhang, F. et al. Concise, scalable and enantioselective total synthesis of prostaglandins. Nat. Chem. 13, 692–697 (2021). · DOI
  40. Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017). · DOI · Paper page
  41. Zhang, X. et al. An atomic structure of the human spliceosome. Cell 169, 918–929.e914 (2017). · DOI
  42. Wang, N. et al. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell 184, 370–383.e313 (2021). · DOI
  43. Kooistra, A. J. et al. GPCRdb in 2021: integrating GPCR sequence, structure and function. Nucleic Acids Res. 49, D335–d343 (2021). · DOI · Paper page
  44. Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D. Struct. Biol. 75, 861–877 (2019). · DOI · Paper page
  45. Moriarty, N. W., Grosse-Kunstleve, R. W. & Adams, P. D. electronic Ligand Builder and Optimization Workbench (eLBOW): a tool for ligand coordinate and restraint generation. Acta Crystallogr. D. Biol. Crystallogr. 65, 1074–1080 (2009). · DOI
  46. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D. Biol. Crystallogr. 60, 2126–2132 (2004). · DOI · Paper page

Metadata

Authors
Lv, X., Gao, K., Nie, J., Zhang, X., Zhang, S., Ren, Y., Sun, X., Li, Q., Huang, J., Liu, L., Zhang, X., Zhang, W., & Liu, X.
Affiliations
  • Xiangya Hospital Central South University (CN)
  • Center for Life Sciences (CN)
  • Tsinghua University (CN)
  • Peking University (CN)
Corresponding author
  • Zhang, Weishe
  • Liu, Xiangyu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-12-08
Volume
14
Issue
1
Pages
8136-8136
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-43922-8
PMC
PMC10709307
OpenAlex
W4389485254
Cited by
19
References
2
Citations by year
2026: 3 · 2025: 14 · 2024: 2
FWCI
1.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81974236; 3212204)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
prostaglandin F2alpha receptor, FP receptor, carboprost, latanoprost, G protein coupling, receptor structure, postpartum hemorrhage, prostaglandin receptors, ligand selectivity
MeSH terms
Latanoprost, Carboprost, Female, Humans, Ligands, Prostaglandins, Receptors, Prostaglandin, Dinoprost, Cryoelectron Microscopy

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