# ALX/FPR2 Receptor Activation by Inflammatory (fMLFII) and Pro-resolving (LXA4 and RvD3) Agonists

## TL;DR

This study explores how the ALX/FPR2 receptor is activated by different agonists, revealing key residues and interactions involved in both pro-inflammatory and pro-resolving signaling.

## Contribution

The study provides new insights into ALX/FPR2 receptor activation mechanisms using molecular simulations and binding energy analysis.

## Key findings

- LXA4 and fMLFII maintain the ALX/FPR2 receptor in an active state longer than RvD3.
- Residues R201 and R205 are key in receptor activation across all agonists.
- Only fMLFII interacts with residue D106, and electrostatic interactions are crucial for agonist binding.

## Abstract

Nine structures of the ALX/FPR2 receptor are currently
deposited
in the PDB. In seven structures, the receptor is complexed with formylated
peptides. In all seven structures, residue D106 is indicated as acting
in the ALX/FPR2 receptor activation in addition to residues R201 and
R205. Here, we performed docking simulations and long-term molecular
dynamics simulations to investigate the ALX/FPR2 receptor activation
using two pro-resolution agonists (lipoxin A4 (LXA4) and
resolvin D3 (RvD3)) and a formylated peptide pro-inflammatory agonist
(fMLFII). We have analyzed the receptor’s activation state,
electrostatic interactions, and the binding affinities of the complexes
receptor-agonist using the MM/PBSA approach. The results showed that
LXA4 and fMLFII kept the receptor in an active state by
a higher simulation time when compared to RvD3. Only R201 and R205
were considered key residues in the ALX/FPR2 receptor activation by
all agonists. The electrostatic interaction analysis confirmed the
importance of these residues in ALX/FPR2 receptor activation. Furthermore,
only fMLLII showed interactions with residue D106. The binding free
energy calculations indicated that the electrostatic component significantly
binds the agonists to the receptor. Overall, the results from this
study provide new insights into the ALX/FPR2 receptor activation mechanisms,
reinforcing the role of critical residues and interactions in the
binding of pro-resolution and inflammatory agonists.