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

Nature communications 2022 Sep 05

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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. © 2022. The Author(s).

Citation

Geng Chen, Xiankun Wang, Qiwen Liao, Yunjun Ge, Haizhan Jiao, Qiang Chen, Yezhou Liu, Wenping Lyu, Lizhe Zhu, Gydo C P van Zundert, Michael J Robertson, Georgios Skiniotis, Yang Du, Hongli Hu, Richard D Ye. Structural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns. Nature communications. 2022 Sep 05;13(1):5232