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

Nature Communications
Tong ChenBeili Wu

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.

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Citations

Apr 3, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yunjun GeRichard D Ye
Sep 22, 2020·British Journal of Pharmacology·Mauro Perretti, Catherine Godson
Mar 7, 2021·International Journal of Molecular Sciences·Jan Jakubík, Esam E El-Fakahany
Oct 17, 2020·Acta Pharmacologica Sinica·Yun-Jun GeRichard D Ye
Mar 1, 2021·Biophysical Journal·Brennica MarlowJens Meiler
Aug 10, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Shuo ZhangRichard D Ye
Apr 12, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Darrell Andrews, Catherine Godson
Apr 20, 2021·The FEBS Journal·Daniel Hilger
Aug 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Heng LiuCheng Zhang
Aug 18, 2021·Clinical Science·William S Powell
Oct 9, 2020·The Journal of Physical Chemistry Letters·Vinicius Schmitz NunesOdonírio Abrahão

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Methods Mentioned

BETA
competition binding
PCR
transfection
size-exclusion chromatography
saturation binding
flow cytometry

Software Mentioned

Schrödinger suite
Induced Fit Docking ( IFD )
XDS
Protein Preparation Wizard
OPLS3
BUSTER
PHENIX
COOT
Genewiz
LigPlot +

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