Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2

Youwen Zhuang,Cheng Zhang,Lei Wang,Jia Guo,Dapeng Sun,Yue Wang,Weiyi Liu,H Eric Xu

doi:10.1038/s41467-022-28586-0

Abstract

The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. Pharmacological targeting of FPRs represents a novel therapeutic approach in treating inflammatory diseases. However, the molecular mechanisms underlying FPR ligand recognition are elusive. We report cryo-EM structures of Gi-coupled FPR1 and FPR2 bound to a formylpeptide and Gi-coupled FPR2 bound to two synthetic peptide and small-molecule agonists. Together with mutagenesis data, our structures reveal the molecular mechanism of formylpeptide recognition by FPRs and structural variations of FPR1 and FPR2 leading to their different ligand preferences. Structural analysis also suggests that diverse FPR agonists sample a conserved activation chamber at the bottom of ligand-binding pockets to activate FPRs. Our results provide a basis for rational drug design on FPRs.

Highlights

The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells
The structures of FPR2-Gi complexes with fMLFII, CGEN-855A, and C43 were determined to global resolutions of 3.1, 2.9, and 3.0 Å, respectively, and the structure of the fMLFII-bound FPR1-Gi complex was determined to 3.2 Å (Fig. 1, Supplementary Fig. 2 and 3, Supplementary Table 1). fMLFII is a potent formylpeptide agonist for both FPR1 and FPR232
FPR2-Gi complexes with four agonists, WKYMVm, fMLFII, CGEN-885A, and C43, revealed interesting features of agonist binding to these two FPRs

Summary

Introduction

The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells They can sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. In the past two decades, numerous studies have found that FPR1 and FPR2, especially FPR2, exhibit unusual functional promiscuity They can recognize a variety of chemically distinct endogenous ligands including proteins and lipids besides formylpeptides and play multifaceted roles in inflammation[2,3,9,10]. Biased FPR2 agonists that can actively resolve inflammation represent a novel therapeutic frontier for various inflammatory pathologies including asthma and cardiovascular diseases[15,21,25,26] To this end, several synthetic FPR2 agonists including peptides and small molecules have been developed and evaluated in pre-clinical and clinical settings[20,27–29]

Methods

Results

Conclusion