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 van Zundert; Michael J Robertson; Georgios Skiniotis; Yang Du; Hongli Hu; Richard D Ye

doi:10.1038/s41467-022-32822-y

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.

Authors

Geng Chen^#¹, Xiankun Wang^#¹, Qiwen Liao^#¹, Yunjun Ge^#^{1

2}, Haizhan Jiao^{1

2}, Qiang Chen¹, Yezhou Liu^{1

3}, Wenping Lyu⁴, Lizhe Zhu⁴, Gydo C P van Zundert⁵, Michael J Robertson⁶, Georgios Skiniotis^{6

7}, Yang Du⁸, Hongli Hu⁹, Richard D Ye¹⁰

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. yangdu@cuhk.edu.cn.
⁹ Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. honglihu@cuhk.edu.cn.
¹⁰ Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. richardye@cuhk.edu.cn.

^# Contributed equally.

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 R201^5.38XXXR205^5.42 (RGIIR) motif for formyl group interaction and receptor activation. This motif works together with D106^3.33 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chemotactic Factors / metabolism
Escherichia coli / genetics
Escherichia coli / metabolism
Humans
N-Formylmethionine Leucyl-Phenylalanine / chemistry
Neutrophils / metabolism
Pathogen-Associated Molecular Pattern Molecules* / metabolism
Peptides / metabolism
Staphylococcus aureus* / metabolism

Substances

Chemotactic Factors
Pathogen-Associated Molecular Pattern Molecules
Peptides
N-Formylmethionine Leucyl-Phenylalanine