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Structural basis for activation of the growth hormone-releasing hormone receptor

Author

Listed:
  • Fulai Zhou

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Huibing Zhang

    (Zhejiang University School of Medicine)

  • Zhaotong Cong

    (Fudan University)

  • Li-Hua Zhao

    (Chinese Academy of Sciences)

  • Qingtong Zhou

    (ShanghaiTech University)

  • Chunyou Mao

    (Zhejiang University School of Medicine)

  • Xi Cheng

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Dan-Dan Shen

    (Zhejiang University School of Medicine)

  • Xiaoqing Cai

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Cheng Ma

    (Zhejiang University School of Medicine)

  • Yuzhe Wang

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

  • Antao Dai

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Yan Zhou

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Wen Sun

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

  • Fenghui Zhao

    (Fudan University)

  • Suwen Zhao

    (ShanghaiTech University
    ShanghaiTech University)

  • Hualiang Jiang

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

  • Yi Jiang

    (Chinese Academy of Sciences)

  • Dehua Yang

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

  • H. Eric Xu

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

  • Yan Zhang

    (Zhejiang University School of Medicine)

  • Ming-Wei Wang

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

Abstract

Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g., isolated growth hormone deficiency, IGHD), gigantism, lipodystrophy and certain cancers. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein at 2.6 Å. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the α-helical GHRH forms an extensive and continuous network of interactions involving all the extracellular loops (ECLs), all the transmembrane (TM) helices except TM4, and the extracellular domain (ECD) of GHRHR, especially the N-terminus of GHRH that engages a broad set of specific interactions with the receptor. Mutagenesis and molecular dynamics (MD) simulations uncover detailed mechanisms by which IGHD-causing mutations lead to the impairment of GHRHR function. Our findings provide insights into the molecular basis of peptide recognition and receptor activation, thereby facilitating the development of structure-based drug discovery and precision medicine.

Suggested Citation

  • Fulai Zhou & Huibing Zhang & Zhaotong Cong & Li-Hua Zhao & Qingtong Zhou & Chunyou Mao & Xi Cheng & Dan-Dan Shen & Xiaoqing Cai & Cheng Ma & Yuzhe Wang & Antao Dai & Yan Zhou & Wen Sun & Fenghui Zhao , 2020. "Structural basis for activation of the growth hormone-releasing hormone receptor," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18945-0
    DOI: 10.1038/s41467-020-18945-0
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    Cited by:

    1. Fenghui Zhao & Qingtong Zhou & Zhaotong Cong & Kaini Hang & Xinyu Zou & Chao Zhang & Yan Chen & Antao Dai & Anyi Liang & Qianqian Ming & Mu Wang & Li-Nan Chen & Peiyu Xu & Rulve Chang & Wenbo Feng & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yingna Xu & Wenbo Feng & Qingtong Zhou & Anyi Liang & Jie Li & Antao Dai & Fenghui Zhao & Jiahui Yan & Chuan-Wei Chen & Hao Li & Li-Hua Zhao & Tian Xia & Yi Jiang & H. Eric Xu & Dehua Yang & Ming-Wei , 2022. "A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Li-Hua Zhao & Jingyu Lin & Su-Yu Ji & X. Edward Zhou & Chunyou Mao & Dan-Dan Shen & Xinheng He & Peng Xiao & Jinpeng Sun & Karsten Melcher & Yan Zhang & Xiao Yu & H. Eric Xu, 2022. "Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Yan Chen & Qingtong Zhou & Jiang Wang & Youwei Xu & Yun Wang & Jiahui Yan & Yibing Wang & Qi Zhu & Fenghui Zhao & Chenghao Li & Chuan-Wei Chen & Xiaoqing Cai & Ross A .D. Bathgate & Chun Shen & H. Eri, 2023. "Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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