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Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2

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  • Youwen Zhuang

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Lei Wang

    (University of Pittsburgh School of Medicine, University of Pittsburgh)

  • Jia Guo

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Dapeng Sun

    (University of Pittsburgh School of Medicine, University of Pittsburgh)

  • Yue Wang

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Weiyi Liu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • H. Eric Xu

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Cheng Zhang

    (University of Pittsburgh School of Medicine, University of Pittsburgh)

Abstract

The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. Pharmacological targeting of FPRs represents a novel therapeutic approach in treating inflammatory diseases. However, the molecular mechanisms underlying FPR ligand recognition are elusive. We report cryo-EM structures of Gi-coupled FPR1 and FPR2 bound to a formylpeptide and Gi-coupled FPR2 bound to two synthetic peptide and small-molecule agonists. Together with mutagenesis data, our structures reveal the molecular mechanism of formylpeptide recognition by FPRs and structural variations of FPR1 and FPR2 leading to their different ligand preferences. Structural analysis also suggests that diverse FPR agonists sample a conserved activation chamber at the bottom of ligand-binding pockets to activate FPRs. Our results provide a basis for rational drug design on FPRs.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28586-0
    DOI: 10.1038/s41467-022-28586-0
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    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.

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