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Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)

Author

Listed:
  • Yan Chen

    (Fudan University)

  • Qingtong Zhou

    (Fudan University)

  • Jiang Wang

    (Chinese Academy of Sciences
    Lingang Laboratory
    Hangzhou Institute for Advanced Study, UCAS)

  • Youwei Xu

    (Chinese Academy of Sciences)

  • Yun Wang

    (Genova Biotech (Changzhou) Co., Ltd)

  • Jiahui Yan

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

  • Yibing Wang

    (Chinese Academy of Sciences)

  • Qi Zhu

    (Genova Biotech (Changzhou) Co., Ltd)

  • Fenghui Zhao

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Chenghao Li

    (Chinese Academy of Sciences
    Hangzhou Institute for Advanced Study, UCAS)

  • Chuan-Wei Chen

    (Research Center for Deepsea Bioresources)

  • Xiaoqing Cai

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Ross A .D. Bathgate

    (University of Melbourne
    University of Melbourne)

  • Chun Shen

    (Genova Biotech (Changzhou) Co., Ltd)

  • H. Eric Xu

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

  • Dehua Yang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Research Center for Deepsea Bioresources)

  • Hong Liu

    (Chinese Academy of Sciences
    Hangzhou Institute for Advanced Study, UCAS
    University of Chinese Academy of Sciences
    ShanghaiTech University)

  • Ming-Wei Wang

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

Abstract

Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs). Here, we report three cryo-electron microscopy structures of RXFP4–Gi protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053. The B chain of INSL5 adopts a single α-helix that penetrates into the orthosteric pocket, while the A chain sits above the orthosteric pocket, revealing a peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. Our findings not only provide insights into ligand recognition and subtype selectivity among class A G protein-coupled receptors, but also expand the knowledge of signaling mechanisms in the insulin superfamily.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36182-z
    DOI: 10.1038/s41467-023-36182-z
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