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Structural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns

Author

Listed:
  • Geng Chen

    (The Chinese University of Hong Kong)

  • Xiankun Wang

    (The Chinese University of Hong Kong)

  • Qiwen Liao

    (The Chinese University of Hong Kong)

  • Yunjun Ge

    (The Chinese University of Hong Kong
    University of Science and Technology of China)

  • Haizhan Jiao

    (The Chinese University of Hong Kong
    University of Science and Technology of China)

  • Qiang Chen

    (The Chinese University of Hong Kong)

  • Yezhou Liu

    (The Chinese University of Hong Kong
    Shenzhen Bay Laboratory)

  • Wenping Lyu

    (The Chinese University of Hong Kong)

  • Lizhe Zhu

    (The Chinese University of Hong Kong)

  • Gydo C. P. Zundert

    (Schrödinger)

  • Michael J. Robertson

    (Stanford University School of Medicine)

  • Georgios Skiniotis

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Yang Du

    (The Chinese University of Hong Kong)

  • Hongli Hu

    (The Chinese University of Hong Kong)

  • Richard D. Ye

    (The Chinese University of Hong Kong)

Abstract

The formyl peptide receptor 1 (FPR1) is primarily responsible for detection of short peptides bearing N-formylated methionine (fMet) that are characteristic of protein synthesis in bacteria and mitochondria. As a result, FPR1 is critical to phagocyte migration and activation in bacterial infection, tissue injury and inflammation. How FPR1 distinguishes between formyl peptides and non-formyl peptides remains elusive. Here we report cryo-EM structures of human FPR1-Gi protein complex bound to S. aureus-derived peptide fMet-Ile-Phe-Leu (fMIFL) and E. coli-derived peptide fMet-Leu-Phe (fMLF). Both structures of FPR1 adopt an active conformation and exhibit a binding pocket containing the R2015.38XXXR2055.42 (RGIIR) motif for formyl group interaction and receptor activation. This motif works together with D1063.33 for hydrogen bond formation with the N-formyl group and with fMet, a model supported by MD simulation and functional assays of mutant receptors with key residues for recognition substituted by alanine. The cryo-EM model of agonist-bound FPR1 provides a structural basis for recognition of bacteria-derived chemotactic peptides with potential applications in developing FPR1-targeting agents.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32822-y
    DOI: 10.1038/s41467-022-32822-y
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    References listed on IDEAS

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