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Structural basis of CXC chemokine receptor 2 activation and signalling

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Listed:
  • Kaiwen Liu

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

  • Lijie Wu

    (ShanghaiTech University)

  • Shuguang Yuan

    (Chinese Academy of Sciences)

  • Meng Wu

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

  • Yueming Xu

    (ShanghaiTech University)

  • Qianqian Sun

    (ShanghaiTech University)

  • Shu Li

    (Chinese Academy of Sciences)

  • Suwen Zhao

    (ShanghaiTech University
    ShanghaiTech University)

  • Tian Hua

    (ShanghaiTech University)

  • Zhi-Jie Liu

    (ShanghaiTech University
    ShanghaiTech University)

Abstract

Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer1. Although ample effort has been invested into the structural investigation of the chemokine receptors and receptor–chemokine recognition2–4, less is known about endogenous chemokine-induced receptor activation and G-protein coupling. Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. Our results reveal a unique shallow mode of binding between CXCL8 and CXCR2, and also show the interactions between CXCR2 and Gi protein. Further structural analysis of the inactive and active states of CXCR2 reveals a distinct activation process and the competitive small-molecule antagonism of chemokine receptors. In addition, our results provide insights into how a G-protein-coupled receptor is activated by an endogenous protein molecule, which will assist in the rational development of therapeutics that target the chemokine system for better pharmacological profiles.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:585:y:2020:i:7823:d:10.1038_s41586-020-2492-5
    DOI: 10.1038/s41586-020-2492-5
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    Cited by:

    1. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. 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.
    3. Naito Ishimoto & Jae-Hyun Park & Kouki Kawakami & Michiko Tajiri & Kenji Mizutani & Satoko Akashi & Jeremy R. H. Tame & Asuka Inoue & Sam-Yong Park, 2023. "Structural basis of CXC chemokine receptor 1 ligand binding and activation," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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