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Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor

Author

Listed:
  • Jia Duan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Peiyu Xu

    (Chinese Academy of Sciences)

  • Huibing Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • Xiaodong Luan

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Tsinghua university
    Tsinghua university)

  • Jiaqi Yang

    (Chinese Academy of Sciences)

  • Xinheng He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Chunyou Mao

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • Dan-Dan Shen

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • Yujie Ji

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xi Cheng

    (Chinese Academy of Sciences)

  • Hualiang Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Lingang Laboratory
    ShanghaiTech University)

  • Yi Jiang

    (Lingang Laboratory
    ShanghaiTech University)

  • Shuyang Zhang

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Tsinghua university
    Tsinghua university)

  • Yan Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • H. Eric Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

Abstract

Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H6157.42 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization.

Suggested Citation

  • Jia Duan & Peiyu Xu & Huibing Zhang & Xiaodong Luan & Jiaqi Yang & Xinheng He & Chunyou Mao & Dan-Dan Shen & Yujie Ji & Xi Cheng & Hualiang Jiang & Yi Jiang & Shuyang Zhang & Yan Zhang & H. Eric Xu, 2023. "Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36170-3
    DOI: 10.1038/s41467-023-36170-3
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    References listed on IDEAS

    as
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