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Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling

Author

Listed:
  • Youwen Zhuang

    (The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute)

  • Heng Liu

    (University of Pittsburgh)

  • X. Edward Zhou

    (Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute)

  • Ravi Kumar Verma

    (Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR))

  • Parker W. de Waal

    (Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute)

  • Wonjo Jang

    (Medical College of Georgia, Augusta University)

  • Ting-Hai Xu

    (Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute)

  • Lei Wang

    (University of Pittsburgh)

  • Xing Meng

    (David Van Andel Advanced Cryo-Electron Microscopy Suite, Van Andel Research Institute)

  • Gongpu Zhao

    (David Van Andel Advanced Cryo-Electron Microscopy Suite, Van Andel Research Institute)

  • Yanyong Kang

    (Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute
    Takeda Research)

  • Karsten Melcher

    (Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute)

  • Hao Fan

    (Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR))

  • Nevin A. Lambert

    (Medical College of Georgia, Augusta University)

  • H. Eric Xu

    (The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute)

  • Cheng Zhang

    (University of Pittsburgh)

Abstract

Formylpeptide receptors (FPRs) as G protein-coupled receptors (GPCRs) can recognize formylpeptides derived from pathogens or host cells to function in host defense and cell clearance. In addition, FPRs, especially FPR2, can also recognize other ligands with a large chemical diversity generated at different stages of inflammation to either promote or resolve inflammation in order to maintain a balanced inflammatory response. The mechanism underlying promiscuous ligand recognition and activation of FPRs is not clear. Here we report a cryo-EM structure of FPR2-Gi signaling complex with a peptide agonist. The structure reveals a widely open extracellular region with an amphiphilic environment for ligand binding. Together with computational docking and simulation, the structure suggests a molecular basis for the recognition of formylpeptides and a potential mechanism of receptor activation, and reveals conserved and divergent features in Gi coupling. Our results provide a basis for understanding the molecular mechanism of the functional promiscuity of FPRs.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14728-9
    DOI: 10.1038/s41467-020-14728-9
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    Cited by:

    1. Geng Chen & Xiankun Wang & Qiwen Liao & Yunjun Ge & Haizhan Jiao & Qiang Chen & Yezhou Liu & Wenping Lyu & Lizhe Zhu & Gydo C. P. Zundert & Michael J. Robertson & Georgios Skiniotis & Yang Du & Hongli, 2022. "Structural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Jinkang Shen & Dongqi Zhang & Yao Fu & Anqi Chen & Xiaoli Yang & Haitao Zhang, 2022. "Cryo-EM structures of human bradykinin receptor-Gq proteins complexes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Youwen Zhuang & Lei Wang & Jia Guo & Dapeng Sun & Yue Wang & Weiyi Liu & H. Eric Xu & Cheng Zhang, 2022. "Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Chongzhao You & Yumu Zhang & Peiyu Xu & Sijie Huang & Wanchao Yin & H. Eric Xu & Yi Jiang, 2022. "Structural insights into the peptide selectivity and activation of human neuromedin U receptors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. 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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