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Agonist-specific FPR1 conformational change prevents receptor recycling and promotes targeted protein degradation

Junlin Wang1,2, Qiwen Liao2,3, Geng Chen2,4

  • 1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, College of Pharmacy, Jinan University, Guangzhou 510632, China.

Acta Pharmaceutica Sinica. B
|May 25, 2026
PubMed

Insights

A novel peptide agonist, fMet-Leu-Phe-Cys (fMLFC), prevents recycling of the formyl peptide receptor 1 (FPR1) and targets it for degradation. This mechanism reduces FPR1-mediated inflammation and acute lung injury.

Area of Science:

  • Cell biology
  • Immunology
  • Structural biology

Background:

  • Cell surface receptor recycling is vital for signaling and membrane transport.
  • Formyl peptide receptor 1 (FPR1) is crucial in host defense and inflammatory responses.

Purpose of the Study:

  • To investigate the effect of the peptide agonist fMet-Leu-Phe-Cys (fMLFC) on FPR1 recycling and signaling.
  • To elucidate the mechanism by which fMLFC influences FPR1 trafficking and degradation.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of the fMLFC-bound FPR1-Gi complex.
  • Site-directed mutagenesis (e.g., F102A, T177A, F178A) to assess the role of key residues in FPR1 recycling.
  • FlAsH-NanoBRET biosensor to compare conformational changes induced by fMLFC and fMLF.
  • In vivo studies using LPS-treated mice to evaluate the effect on acute lung injury.

Main Results:

  • fMLFC binding to FPR1 prevents receptor recycling, diverting it to lysosomes for degradation, unlike the canonical ligand fMLF.
  • The cryo-EM structure revealed specific interactions between fMLFC and FPR1.
  • Mutations at key interaction sites (F102A, T177A, F178A) enhanced FPR1 recycling.
  • fMLFC induces a distinct conformational change in FPR1 compared to fMLF, leading to reduced cell surface expression.
  • fMLFC treatment reduced acute lung injury in a mouse model.

Conclusions:

  • fMLFC acts as a chemical knockdown agent by promoting targeted degradation of FPR1.
  • This targeted degradation effectively reduces FPR1-mediated inflammatory responses and associated pathologies like acute lung injury.
Keywords:
Acute lung injuryCryo-EMFormyl peptide receptorsG protein-coupled receptorsProtein degradationReceptor recyclingSmall GTPasesSorting nexins

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