Abstract
Formylpeptide receptors (FPRs) as G protein-coupled receptors (GPCRs) can recognize formylpeptides derived from pathogens or host cells to function in host defense and cell clearance. In addition, FPRs, especially FPR2, can also recognize other ligands with a large chemical diversity generated at different stages of inflammation to either promote or resolve inflammation in order to maintain a balanced inflammatory response. The mechanism underlying promiscuous ligand recognition and activation of FPRs is not clear. Here we report a cryo-EM structure of FPR2-Gi signaling complex with a peptide agonist. The structure reveals a widely open extracellular region with an amphiphilic environment for ligand binding. Together with computational docking and simulation, the structure suggests a molecular basis for the recognition of formylpeptides and a potential mechanism of receptor activation, and reveals conserved and divergent features in Gi coupling. Our results provide a basis for understanding the molecular mechanism of the functional promiscuity of FPRs.
Highlights
Formylpeptide receptors (FPRs) as G protein-coupled receptors (GPCRs) can recognize formylpeptides derived from pathogens or host cells to function in host defense and cell clearance
Formylpeptides with N-terminal formylated (N-formyl) methionine are abundantly present in bacterial or host mitochondrial proteins. They function as the major chemotactic pathogen- and damage-associated molecular patterns that can be recognized by the family of formylpeptide receptors (FPRs)[1,2]
We performed GTPγS binding assays using cell membranes expressing human FPR2 and purified Gi protein to prove that a synthetic peptide agonist with the sequence Trp-LysTyr-Met-Val-d-Met-NH2 (WKYMVm)[26,27,28] can promote the activation of Gi through FPR2 in a dose-dependent manner (Fig. 1a)
Summary
Formylpeptide receptors (FPRs) as G protein-coupled receptors (GPCRs) can recognize formylpeptides derived from pathogens or host cells to function in host defense and cell clearance. Our results provide a basis for understanding the molecular mechanism of the functional promiscuity of FPRs. Formylpeptides with N-terminal formylated (N-formyl) methionine are abundantly present in bacterial or host mitochondrial proteins. It has been speculated that different endogenous ligands act on FPR2 to induce distinct signaling pathways to either promote or resolve inflammation Because of such complex functional roles, FPR2 has been linked to many inflammation-related diseases, including asthma[17], influenza[18], Alzheimer’s disease[19], and various cardiovascular diseases[20]. The molecular mechanisms underlying promiscuous ligand recognition and multifaceted signaling of FPRs are largely unclear due to a lack of structural understanding of the function of FPRs. Here, we report a cryo-EM structure of human FPR2-Gi signaling complex with a synthetic pro-inflammatory peptide agonist. The results provide structural insights into receptor activation and Gi protein coupling for the FPR family
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