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

Area of Science:

• Structural Biology
• Immunology
• Microbiology

Background:

• Formyl peptide receptor 1 (FPR1) is crucial for detecting N-formylated peptides from bacteria and mitochondria, mediating immune responses like phagocyte migration and activation.
• The precise mechanism by which FPR1 distinguishes formylated from non-formylated peptides has remained unclear.
• FPR1 plays a vital role in host defense against bacterial infections, tissue injury, and inflammation.

Purpose of the Study:

• To elucidate the structural basis of formyl peptide recognition and activation by human FPR1.
• To understand how FPR1 differentiates between formylated and non-formylated peptides.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of the human FPR1-Gi protein complex bound to bacterial peptides.
• Molecular dynamics (MD) simulations and functional assays with mutant receptors were employed to validate the binding model.

Main Results:

• The study reports high-resolution cryo-EM structures of FPR1 bound to bacterial peptides fMet-Ile-Phe-Leu (fMIFL) and fMet-Leu-Phe (fMLF).
• FPR1 adopts an active conformation with a distinct binding pocket featuring the RGIIR motif (R2015.38-R2055.42) essential for N-formyl group interaction and receptor activation.
• Key residues, including D1063.33, form hydrogen bonds with the N-formyl group, establishing a recognition mechanism supported by simulations and functional assays.

Conclusions:

• The cryo-EM structures provide a detailed molecular model for how FPR1 recognizes and binds to bacteria-derived chemotactic peptides.
• This structural understanding offers a foundation for designing novel FPR1-targeting agents for therapeutic applications in infectious and inflammatory diseases.