Premium
Structure and drug development of the human formylpeptide receptors FPR1 and FPR2
Author(s) -
Wang Lei,
Zhuang Youwen,
Sun Dapeng,
Xu Eric H.,
Zhang Cheng
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.0r769
Subject(s) - receptor , drug discovery , ligand (biochemistry) , g protein coupled receptor , drug , biology , mutagenesis , computational biology , microbiology and biotechnology , chemistry , pharmacology , biochemistry , mutant , gene
The formylpeptide receptors (FPRs) mediate pattern recognition of formylated peptides derived from invading pathogens or mitochondria from dead host cells. They can also sense other structurally distinct native peptides and even lipid mediators to either promote or resolve inflammation. Pharmacological targeting of FPRs represents a novel therapeutic approach in treating inflammatory diseases. However, the molecular mechanisms underlying FPR ligand recognition are elusive. We report cryo‐EM structures of G i ‐coupled FPR1 and FPR2 bound to a formylpeptide and G i ‐coupled FPR2 bound to two synthetic peptide and small‐molecule agonists. Together with mutagenesis data, our structures reveal the molecular mechanism of formylpeptide recognition by FPRs and structural variations of FPR1 and FPR2 leading to their different ligand preferences. Structural analysis also suggests that diverse FPR agonists sample a conserved activation chamber at the bottom of ligand‐binding pockets to activate FPRs. Based on our structures, we further screen several new chemicals as potential drugs. Our results provide a basis for structure‐based drug design on FPRs.