2. Academic Validation
  3. Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2

Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2

  • Nat Commun. 2022 Feb 25;13(1):1054. doi: 10.1038/s41467-022-28586-0.
Youwen Zhuang  # 1,  Lei Wang  # 2,  Jia Guo 1 3,  Dapeng Sun 2,  Yue Wang 1 3,  Weiyi Liu 1 3,  H Eric Xu 4 5,  Cheng Zhang 6
Affiliations

Affiliations

  • 1 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
  • 2 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • 3 University of Chinese Academy of Sciences, 100049, Beijing, China.
  • 4 The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China. Eric.Xu@simm.ac.cn.
  • 5 University of Chinese Academy of Sciences, 100049, Beijing, China. Eric.Xu@simm.ac.cn.
  • 6 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. chengzh@pitt.edu.
  • # Contributed equally.
PMID: 35217703 DOI: 10.1038/s41467-022-28586-0
Abstract

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. Our results provide a basis for rational drug design on FPRs.

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