Visual representation of different PAR2 ligand binding pockets and illustration of proposed interaction sites for current antagonist.
The non-peptide AZ3451 (PDB ID:5NDZ) occupies the allosteric pocket. While original data suggests AZ8838 occupies allosteric site [73,74], recent novel agonist-bound models propose AZ8838 binds to the orthosteric pocket [75] (PAR2, PDB ID:5NDD). PAR2-Fab3949 (PDB ID: 5NJ6) engagement on the extracellular interface is presented. The example antagonist peptides shown (FSLLRY-NH2 and LSIGRL-NH2) are proposed to block the ECL-2 region, thus preventing receptor tethered ligand engagement and receptor activation. Pepducins (PZ-235 and P2pal-18S) are cell penetrable lipidated peptides and traverse the cell membrane and have been proposed to exert their inhibitory actions through engagement with the third intracellular loop (ICL-3) of PAR2 [64,66,67]. The non-peptide small molecule I-191 has previously been proposed to be insurmountable and behave as a negative allosteric modulator (NAM) although the exact site of engagement with PAR2 remains to be characterised. Visuals created using Mol* [80] with PDB IDs for 5NDZ, 5NDD and 5NJ6 [73].