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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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    as
    1. Heng Liu & Dapeng Sun & Alexander Myasnikov & Marjorie Damian & Jean-Louis Baneres & Ji Sun & Cheng Zhang, 2021. "Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    2. Tilman Flock & Charles N. J. Ravarani & Dawei Sun & A. J. Venkatakrishnan & Melis Kayikci & Christopher G. Tate & Dmitry B. Veprintsev & M. Madan Babu, 2015. "Universal allosteric mechanism for Gα activation by GPCRs," Nature, Nature, vol. 524(7564), pages 173-179, August.
    3. 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.
    4. 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.
    5. Shuguang Yuan & Slawomir Filipek & Krzysztof Palczewski & Horst Vogel, 2014. "Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    6. Christopher J. Draper-Joyce & Maryam Khoshouei & David M. Thal & Yi-Lynn Liang & Anh T. N. Nguyen & Sebastian G. B. Furness & Hariprasad Venugopal & Jo-Anne Baltos & Jürgen M. Plitzko & Radostin Danev, 2018. "Structure of the adenosine-bound human adenosine A1 receptor–Gi complex," Nature, Nature, vol. 558(7711), pages 559-563, June.
    7. 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.
    8. Youwen Zhuang & Heng Liu & X. Edward Zhou & Ravi Kumar Verma & Parker W. de Waal & Wonjo Jang & Ting-Hai Xu & Lei Wang & Xing Meng & Gongpu Zhao & Yanyong Kang & Karsten Melcher & Hao Fan & Nevin A. L, 2020. "Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    9. Jia Duan & Dan-Dan Shen & Tingting Zhao & Shimeng Guo & Xinheng He & Wanchao Yin & Peiyu Xu & Yujie Ji & Li-Nan Chen & Jinyu Liu & Huibing Zhang & Qiufeng Liu & Yi Shi & Xi Cheng & Hualiang Jiang & H., 2022. "Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    10. Kaiwen Liu & Lijie Wu & Shuguang Yuan & Meng Wu & Yueming Xu & Qianqian Sun & Shu Li & Suwen Zhao & Tian Hua & Zhi-Jie Liu, 2020. "Structural basis of CXC chemokine receptor 2 activation and signalling," Nature, Nature, vol. 585(7823), pages 135-140, September.
    11. Ya Zhu & Xiaowen Lin & Xin Zong & Shuo Han & Mu Wang & Yuxuan Su & Limin Ma & Xiaojing Chu & Cuiying Yi & Qiang Zhao & Beili Wu, 2022. "Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    12. Hideaki E. Kato & Yan Zhang & Hongli Hu & Carl-Mikael Suomivuori & Francois Marie Ngako Kadji & Junken Aoki & Kaavya Krishna Kumar & Rasmus Fonseca & Daniel Hilger & Weijiao Huang & Naomi R. Latorraca, 2019. "Conformational transitions of a neurotensin receptor 1–Gi1 complex," Nature, Nature, vol. 572(7767), pages 80-85, August.
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