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

  • Nat Commun. 2022 Sep 5;13(1):5232. doi: 10.1038/s41467-022-32822-y.
Geng Chen  #  1 ,  Xiankun Wang  #  1 ,  Qiwen Liao  #  1 ,  Yunjun Ge  #  1  2 ,  Haizhan Jiao  1  2 ,  Qiang Chen  1 ,  Yezhou Liu  1  3 ,  Wenping Lyu  4 ,  Lizhe Zhu  4 ,  Gydo C P van Zundert  5 ,  Michael J Robertson  6 ,  Georgios Skiniotis  6  7 ,  Yang Du  8 ,  Hongli Hu  9 ,  Richard D Ye  10
Affiliations
  • 1. Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • 2. School of Life Sciences, University of Science and Technology of China, Anhui, 230026, China.
  • 3. Shenzhen Bay Laboratory, Shenzhen, Guangdong, 518055, China.
  • 4. Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • 5. Schrödinger, New York, NY, 10036, USA.
  • 6. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 7. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 8. Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. [email protected].
  • 9. Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. [email protected].
  • 10. Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. [email protected].
  • # Contributed equally.
PMID: 36064945 DOI: 10.1038/s41467-022-32822-y
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.