The formyl peptide receptors, abbreviated as FPRs in humans, are pattern recognition receptors (PRRs) with central roles in host defense and inflammation [1,11,12,13]. Although expressed in a number of different cell types, the actions of FPRs have primarily been investigated in cells of myeloid origin; human FPR1 and FPR2 were originally identified in neutrophils and monocytes, while FPR3 was only detected in the latter [14]. These receptors have a diverse array of functions, from eliciting cellular adhesion and directed migration of recruited immune cells through chemotaxis, to granule release and superoxide formation [12,15,16]. The importance of these receptors in non-myeloid cell types has been reported more recently [17,18,19].

This receptor class was initially identified and named based on their ability to bind N-formylated peptides such as N-formylmethionine (fMet), produced through the degradation of both bacteria and mitochondria [20,21]. The ability to recognize N-formyl peptides, including the potent FPR1 agonist and chemotactic agent N-formyl-methionyl-leucyl-phenylalanine (fMLF), led to the conclusion that FPRs act as PRRs [3,22]. Following their original description, accumulating evidence has shown FPRs to bind to a diverse and continually expanding repertoire of ligands, including not only N-formyl peptides, but also non-formyl peptides of both microbial and host origin, synthetic small molecules, and eicosanoid lipids (Table 1). These molecules all bind to one or several FPRs and have been reviewed in detail previously [2,12,23].

There are three genes which encode for human FPRs: FPR1, FPR2, and FPR3. All three proteins share similar sequence homology and are encoded by genes clustered together on chromosome 19q13.3 in the human genome (Gao et al., 1998; Yi et al., 2007). Of these receptors, FPR1 and FPR2 share a particularly high overall gene sequence homology, with some overlapping functionality [2]. Comparatively, the genes which encode FPRs vary considerably in number between different species. For example, mice have eight known members of the FPR gene family on chromosome 17A3.2, denoted as ‘Fprs’. Despite the discrepancy in receptor numbers across the two species, several receptors share similar functionality, including FPR1/Fpr1, both of which are known to respond to host infection [59] and regulate chemotaxis [15,60,61]. These similarities extend to human FPR2 as well, although murine functionality is encoded by two receptors which work in synergy to carry out comparable functions: Fpr2/3 [62,63]. Highlighting their parallels, amino acid BLAST alignment confirms that these murine receptors display 76% (Fpr2) and 74% (Fpr3) identity alongside 85% (Fpr2) and 81% (Fpr3) homology to human FPR2, while Fpr2 and Fpr3 display 82% identity and 88% homology to each other.

For many years, the crystalline structure of these receptors remained elusive. Instead, structure simulation and molecular modeling [64], computer-aided ligand docking [65,66] and site-directed mutagenesis [67,68] had led to the identification of amino acids within both FPR1 and FPR2 responsible for receptor interactions with several different molecules [12]. More recently, the crystalline structure for FPR1 bound to the pan-formyl-peptide agonist fMLFII was reported with a resolution of 3.2 Å [69]. Further, two independent research groups reported crystalline structures for human FPR2 bound to the hexapeptide WKYMVm—a strong agonist for the receptor—with resolutions of 2.8 Å and 3.17 Å, respectively [13,70]. Zhaung and colleagues expanded further on the crystalline structure of FPR2, reporting interactions with several other known receptor agonists, fMLFII, the anti-inflammatory peptide CGEN-855A, and the synthetic anti-inflammatory small molecule Compound-43 with 3.1, 2.9 and 3.0 Å resolution, respectively [69]. Interestingly, structural comparison of these receptor-agonist conformations indicate the presence of a conserved receptor activation mechanism, suggesting that despite the ligands’ structural differences, receptor stimulation occurs due to similar molecular interactions. However, while these studies provide novel insights into the binding mechanisms of different ligands, it is crucial that the development of FPR crystalline structures continues, including interactions with receptor antagonists like cyclosporin H and WRW₄, alongside pathogenic ligands such as serum amyloid A and β-amyloid (Aβ). In terms of the latter, cryo-electron microscopy recently helped elucidate the interaction between Aβ_1-42 and FPR2 [71]. However, follow-up research will be important to decipher whether different Aβ formulations—such as monomers, oligomers, or fibrils—display different binding characteristics with this promiscuous receptor.

In summary, identification of novel receptor binding pockets for both pro-resolution and disease associated ligands may prove crucial for the future development of improved FPR associated therapeutics.