Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity
Abstract Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F2α 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 re...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43922-8 |
| _version_ | 1797397903411511296 |
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| author | Xiuqing Lv Kaixuan Gao Jia Nie Xin Zhang Shuhao Zhang Yinhang Ren Xiaoou Sun Qi Li Jingrui Huang Lijuan Liu Xiaowen Zhang Weishe Zhang Xiangyu Liu |
| author_facet | Xiuqing Lv Kaixuan Gao Jia Nie Xin Zhang Shuhao Zhang Yinhang Ren Xiaoou Sun Qi Li Jingrui Huang Lijuan Liu Xiaowen Zhang Weishe Zhang Xiangyu Liu |
| author_sort | Xiuqing Lv |
| collection | DOAJ |
| description | Abstract Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F2α 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. |
| first_indexed | 2024-03-09T01:17:56Z |
| format | Article |
| id | doaj.art-c59730ff2a0b4482b89bbca0374da029 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T01:17:56Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c59730ff2a0b4482b89bbca0374da0292023-12-10T12:23:15ZengNature PortfolioNature Communications2041-17232023-12-0114111110.1038/s41467-023-43922-8Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivityXiuqing Lv0Kaixuan Gao1Jia Nie2Xin Zhang3Shuhao Zhang4Yinhang Ren5Xiaoou Sun6Qi Li7Jingrui Huang8Lijuan Liu9Xiaowen Zhang10Weishe Zhang11Xiangyu Liu12Department of Obstetrics, Xiangya Hospital Central South UniversityState Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua UniversityDepartment of Obstetrics, Xiangya Hospital Central South UniversityState Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua UniversityState Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua UniversityState Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua UniversityBeijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua UniversityReproductive Medicine Center, Xiangya Hospital Central South UniversityDepartment of Obstetrics, Xiangya Hospital Central South UniversityDepartment of Obstetrics, Xiangya Hospital Central South UniversityDepartment of Obstetrics, Xiangya Hospital Central South UniversityDepartment of Obstetrics, Xiangya Hospital Central South UniversityState Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua UniversityAbstract Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F2α 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.https://doi.org/10.1038/s41467-023-43922-8 |
| spellingShingle | Xiuqing Lv Kaixuan Gao Jia Nie Xin Zhang Shuhao Zhang Yinhang Ren Xiaoou Sun Qi Li Jingrui Huang Lijuan Liu Xiaowen Zhang Weishe Zhang Xiangyu Liu Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity Nature Communications |
| title | Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity |
| title_full | Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity |
| title_fullStr | Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity |
| title_full_unstemmed | Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity |
| title_short | Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity |
| title_sort | structures of human prostaglandin f2α receptor reveal the mechanism of ligand and g protein selectivity |
| url | https://doi.org/10.1038/s41467-023-43922-8 |
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