Formylpeptide receptor 2: Nomenclature, structure, signalling and translational perspectives: IUPHAR review 35

Abstract

We discuss the fascinating pharmacology of formylpeptide receptor 2 (FPR2; often referred to as FPR2/ALX since it binds lipoxin A₄ ). Initially identified as a low-affinity 'relative' of FPR1, FPR2 presents complex and diverse biology. For instance, it is activated by several classes of agonists (from peptides to proteins and lipid mediators) and displays diverse expression patterns on myeloid cells as well as epithelial cells and endothelial cells, to name a few. Over the last decade, the pharmacology of FPR2 has progressed from being considered a weak chemotactic receptor to a master-regulator of the resolution of inflammation, the second phase of the acute inflammatory response. We propose that exploitation of the biology of FPR2 offers innovative ways to rectify chronic inflammatory states and represents a viable avenue to develop novel therapies. Recent elucidation of FPR2 structure will facilitate development of the anti-inflammatory and pro-resolving drugs of next decade.

Keywords: ALXR; FPR; N-formylated peptides; annexin-A1; lipoxin A4; resolution of inflammation.

FIGURE 1

Summary illustration of the chemical diversity of FPR agonists across the three human receptor subtypes with their known anti‐inflammatory versus pro‐inflammatory consequences (see text for references). Abbreviations: Ac‐AnxA1_2‐26, annexin 1‐(2‐26); Cmpd, compound; CRAMP, cathelicidin‐related antimicrobial peptide; RvD, resolvin; SSA, serum amyloid A.

FIGURE 2

Agonist bound FPR2‐G_i1 and FPR1‐G_i1 complexes. (a) Left: the first FPR2 cryo‐EM structure (PDB:6OMM) bound to the peptide agonist WKYMVm and the heterotrimeric Gi₁ protein. The large inset on the right shows a close up of the WKYMVm binding site, with interacting FPR2 residues shown. H‐bonds and salt bridges between the receptor and the peptide are shown as black and red dashed lines, respectively. The regions highlighted in the green and pink circles show the hydrophobic clusters of residues at the top and bottom of the binding pocket. (b) Left: overlay of four agonist bound FPR2 cryo‐EM structures (PDBs: 6OMM, 7T6V, 7T6U, 7T6S) reveals different agonists bind in overlapping poses and induces a similar FPR2 conformation. Right insets show a close up of the binding sites of fMLFII (top left), compound 43 (bottom left) and CGEN 855 with interacting FPR2 residues shown. (c) Left: overlay of the cryo‐EM structures of FPR1 (PDB:7T6T) and FPR2 (PDB:7T6V) shows similar binding poses of fMLFII in both receptors. White arrows highlight differences in the conformation of the two receptors when fMLFII is bound. Middle and right: surface representation coloured by electrostatic charge (blue, positively charged; white, neutral; red, negatively charged) of the FPR2 (middle, with fMLFII and WKYMVm bound) and FPR1 (right, with fMLFII bound) looking down from the extracellular surface into the peptide binding pocket. This highlights the large open and negatively charged FPR2 binding pocket, relative to the more closed, positively charged FPR1 binding cavity. The top of the FPR2 binding pocket that accommodates the side chain of lysine 2 (K2) of WKYMVm is predominantly negatively charged, providing a rationale for the preference of for positively charged over negatively charged residues within the C‐terminus of FPR2 peptide agonists.