Session: 697 Modeling, Mutations, and Structural Studies
(697.7) Structure and drug development of the human formylpeptide receptors FPR1 and FPR2
Monday, April 4, 2022
10:00 AM – 12:00 PM
Location: Exhibit/Poster Hall A-B - Pennsylvania Convention Center
Poster Board Number: B89
Lei Wang (University of Pittsburgh), Youwen Zhuang (Chinese Academy of Sciences), Dapeng Sun (University of Pittsburgh), Eric Xu (Chinese Academy of Sciences), Cheng Zhang (University of Pittsburgh)
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 Gi-coupled FPR1 and FPR2 bound to a formylpeptide and Gi-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.
The National Institutes of Health (NIH) grants 1R03TR003306-01A1 and 1R35GM128641
Overall structures of the Gi-coupled FPR1 and FPR2 complexes