1. Structural basis of ligand binding modes at the human formyl peptide receptor 2
- Author
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Xin Zong, Cuiying Yi, Hui Zhang, Yechun Xu, Qiang Zhao, Limin Ma, Yunjun Ge, Tong Chen, Beili Wu, Gye Won Han, Muya Xiong, Mu Wang, and Richard D. Ye
- Subjects
0301 basic medicine ,Agonist ,Protein Conformation ,medicine.drug_class ,Science ,General Physics and Astronomy ,Peptide ,Ligands ,Article ,General Biochemistry, Genetics and Molecular Biology ,Formyl peptide receptor 2 ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,G protein-coupled receptors ,medicine ,Humans ,Amino Acid Sequence ,Receptors, Lipoxin ,lcsh:Science ,Peptide sequence ,X-ray crystallography ,G protein-coupled receptor ,chemistry.chemical_classification ,Binding Sites ,Multidisciplinary ,Formyl peptide receptor ,Chemistry ,Chemotaxis ,General Chemistry ,Ligand (biochemistry) ,Receptors, Formyl Peptide ,Molecular Docking Simulation ,N-Formylmethionine Leucyl-Phenylalanine ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Biophysics ,lcsh:Q ,Signal Transduction - Abstract
The human formyl peptide receptor 2 (FPR2) plays a crucial role in host defense and inflammation, and has been considered as a drug target for chronic inflammatory diseases. A variety of peptides with different structures and origins have been characterized as FPR2 ligands. However, the ligand-binding modes of FPR2 remain elusive, thereby limiting the development of potential drugs. Here we report the crystal structure of FPR2 bound to the potent peptide agonist WKYMVm at 2.8 Å resolution. The structure adopts an active conformation and exhibits a deep ligand-binding pocket. Combined with mutagenesis, ligand binding and signaling studies, key interactions between the agonist and FPR2 that govern ligand recognition and receptor activation are identified. Furthermore, molecular docking and functional assays reveal key factors that may define binding affinity and agonist potency of formyl peptides. These findings deepen our understanding about ligand recognition and selectivity mechanisms of the formyl peptide receptor family., Formyl peptide receptors (FPRs) are GPCRs that play important roles in transducing chemotactic signals in phagocytes and mediating host-defense and inflammatory responses. Here the authors present the 2.8 Å crystal structure of human FPR2 in complex with the peptide agonist WKYMVm and in combination with molecular docking, ligand-binding and signalling assays provide further insights into the binding modes of FPR2 to both non-formyl and formyl peptides.
- Published
- 2020