Structural basis for signal recognition and transduction by platelet-activating-factor receptor

• Published in: Nature structural & molecular biology Vol. 25; no. 6; pp. 488 - 495
• Main Authors: Cao, Can, Tan, Qiuxiang, Xu, Chanjuan, He, Lingli, Yang, Linlin, Zhou, Ye, Zhou, Yiwei, Qiao, Anna, Lu, Minmin, Yi, Cuiying, Han, Gye Won, Wang, Xianping, Li, Xuemei, Yang, Huaiyu, Rao, Zihe, Jiang, Hualiang, Zhao, Yongfang, Liu, Jianfeng, Stevens, Raymond C., Zhao, Qiang, Zhang, Xuejun C., Wu, Beili
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2018; Nature Publishing Group
• Subjects: 13/1; 13/95; 14/34; 38/70; 42/109; 45/77; 631/45/535/1266; 631/45/612/1237; 631/45/612/194; 631/80/86; 82/16; 82/80; 82/83; Antagonists (Biochemistry); Asthma; Binding Sites; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Biophysics; Cardiovascular diseases; Cell interactions; Cell receptors; Cellular signal transduction; Composition; Crystal structure; Crystallography, X-Ray; Fluorescence Resonance Energy Transfer; G protein-coupled receptors; G proteins; Health aspects; Heart diseases; Helices; Humans; Hydrogen Bonding; Imidazoles - pharmacology; Indoles - pharmacology; Inflammation; Laboratories; Life Sciences; Ligands; Membrane Biology; Molecular biology; Molecular docking; Molecular Docking Simulation; Mutation; Observations; Phospholipids; Physiological effects; Platelet activating factor; Platelet Aggregation Inhibitors - pharmacology; Platelet Membrane Glycoproteins - agonists; Platelet Membrane Glycoproteins - antagonists & inhibitors; Platelet Membrane Glycoproteins - chemistry; Platelet Membrane Glycoproteins - metabolism; Protein Conformation; Protein Structure; Proteins; Receptors; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Recognition; Signal Transduction; Structure; Thiazoles - pharmacology; China
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-018-0068-y

Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here we report crystal structures of human PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491 at 2.8-Å and 2.9-Å resolution, respectively. The structures, supported by molecular docking of PAF, provide insights into the signal-recognition mechanisms of PAFR. The PAFR–SR 27417 structure reveals an unusual conformation showing that the intracellular tips of helices II and IV shift outward by 13 Å and 4 Å, respectively, and helix VIII adopts an inward conformation. The PAFR structures, combined with single-molecule FRET and cell-based functional assays, suggest that the conformational change in the helical bundle is ligand dependent and plays a critical role in PAFR activation, thus greatly extending knowledge about signaling by G-protein-coupled receptors.
Crystal structures of PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491, together with accompanying experiments, provide insight into recognition of PAF and reveal an unusual ligand-dependent conformation of helical bundle.