Structural basis of ligand binding modes at the human formyl peptide receptor 2

Tong Chen, Muya Xiong, Xin Zong, Yunjun Ge, Hui Zhang, Mu Wang, Gye Won Han, Cuiying Yi, Limin Ma, Richard D. Ye, Yechun Xu (), Qiang Zhao () and Beili Wu ()
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Tong Chen: Chinese Academy of Sciences
Muya Xiong: Chinese Academy of Sciences
Xin Zong: Chinese Academy of Sciences
Yunjun Ge: University of Macau
Hui Zhang: Chinese Academy of Sciences
Mu Wang: Chinese Academy of Sciences
Gye Won Han: University of Southern California
Cuiying Yi: Chinese Academy of Sciences
Limin Ma: Chinese Academy of Sciences
Richard D. Ye: The Chinese University of Hong Kong
Yechun Xu: Chinese Academy of Sciences
Qiang Zhao: Chinese Academy of Sciences
Beili Wu: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15009-1

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