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

Author

Listed:
  • Xiuqing Lv

    (Xiangya Hospital Central South University)

  • Kaixuan Gao

    (Tsinghua University
    Tsinghua University)

  • Jia Nie

    (Xiangya Hospital Central South University)

  • Xin Zhang

    (Tsinghua University
    Tsinghua University)

  • Shuhao Zhang

    (Tsinghua University
    Tsinghua University)

  • Yinhang Ren

    (Tsinghua University
    Tsinghua University)

  • Xiaoou Sun

    (Tsinghua University
    Tsinghua University)

  • Qi Li

    (Xiangya Hospital Central South University)

  • Jingrui Huang

    (Xiangya Hospital Central South University)

  • Lijuan Liu

    (Xiangya Hospital Central South University)

  • Xiaowen Zhang

    (Xiangya Hospital Central South University)

  • Weishe Zhang

    (Xiangya Hospital Central South University
    Hunan Engineering Research Center of Early Life Development and Disease Prevention)

  • Xiangyu Liu

    (Tsinghua University
    Tsinghua University
    Peking University)

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.

Suggested Citation

  • 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, 2023. "Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43922-8
    DOI: 10.1038/s41467-023-43922-8
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    References listed on IDEAS

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