Phase Plate Cryo-Em Structure Of Formylpeptide Receptor 2 Bound To An Inhibitory G Protein

Formylpeptide receptors (FPRs) are pattern recognition G protein-coupled receptors that can recognize formylpeptides derived from pathogens or host cells. In addition, they can also recognize structurally and functionally distinct peptides and lipids to either promote or resolve inflammation. The molecular mechanisms underlying the pattern recognition and multifaceted signaling of FPRs are not clear. Here we report a cryo-EM structure of formylpeptide receptor 2 (FPR2) and Gi complex with a peptide agonist. The structure reveals a widely open extracellular region with an amphiphilic environment, providing a structural basis for promiscuous ligand recognition. Together with computational docking and simulation, the structure suggests molecular mechanisms for the pattern recognition of formylpeptides by FPRs and receptor activation by diverse agonists and reveals conserved and divergent features in Gi coupling.