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

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 Hu () and Richard D. Ye ()
Additional contact information
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
Haizhan Jiao: The Chinese University of Hong Kong
Qiang Chen: The Chinese University of Hong Kong
Yezhou Liu: The Chinese University of Hong Kong
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32822-y

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