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Nat Struct Mol Biol. 2018 Jun;25(6):488-495. doi: 10.1038/s41594-018-0068-y. Epub 2018 May 28.

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

Cao C1,2, Tan Q3,4,2, Xu C5, He L1, Yang L6, Zhou Y1,2, Zhou Y5, Qiao A4,2, Lu M4,2, Yi C3, Han GW7, Wang X1, Li X1, Yang H8, Rao Z1, Jiang H3,4,8, Zhao Y1, Liu J5, Stevens RC9,10, Zhao Q3,4,2,11, Zhang XC12,13, Wu B14,15,16,17.

Author information

1
National Laboratory of Biomacromolecules, National Center of Protein Science-Beijing, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
2
University of Chinese Academy of Sciences, Beijing, China.
3
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
5
College of Life Science and Technology, Collaborative Innovation Center for Genetics and Development, and Key Laboratory of Molecular Biophysics of the Ministry of Education, Huazhong University of Science and Technology, Wuhan, China.
6
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
7
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA, USA.
8
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
9
iHuman Institute, ShanghaiTech University, Shanghai, China.
10
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
11
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China.
12
National Laboratory of Biomacromolecules, National Center of Protein Science-Beijing, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhangc@ibp.ac.cn.
13
University of Chinese Academy of Sciences, Beijing, China. zhangc@ibp.ac.cn.
14
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. beiliwu@simm.ac.cn.
15
University of Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.
16
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. beiliwu@simm.ac.cn.
17
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, China. beiliwu@simm.ac.cn.

Abstract

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.

PMID:
29808000
DOI:
10.1038/s41594-018-0068-y

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