Insights into the Activation Mechanism of the ALX/FPR2 Receptor

The formyl peptide receptor 2 (ALX/FPR2), a G-protein-coupled receptor (GPCR), plays an important role in host defense and inflammation. This receptor can be driven as pro- or anti-inflammatory depending on its agonist, such as N-formyl-Met-Leu-Phe-Lys (fMLFK) and resolvin D1 (RvD1) or its aspirin-triggered 17 (R)-epimer, AT-RvD1, respectively. However, the activation mechanism of ALX/FPR2 by pro- and anti-inflammatory agonists remains unclear. In this work, on the basis of molecular dynamics simulations, we evaluated a model of the ALX/FPR2 receptor activation process using two agonists, fMLFK and AT-RvD1, with opposite effects. The simulations by both fMLFK and AT-RvD1 induced the ALX/FPR2 activation through a set of receptor-core residues, in particular, R205, Q258, and W254. In addition, the activation was dependent on the disruption of electrostatic interactions in the cytoplasmic region of the receptor. We also found that in the AT-RvD1 simulations, the position of the H8 helix was similar to that of the same helix in other class-A GPCRs coupled to arrestin. Thus our results shed light on the mechanism of activation of the ALX/FPR2 receptor by pro-inflammatory and pro-resolution agonists.