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

被引：62

作者：

Cao, Can ^{[1
,4
]}

Tan, Qiuxiang ^{[2
,3
,4
]}

Xu, Chanjuan ^{[5
,6
]}

He, Lingli ^{[1
]}

Yang, Linlin ^{[7
]}

Zhou, Ye ^{[1
,4
]}

Zhou, Yiwei ^{[5
,6
]}

Qiao, Anna ^{[3
,4
]}

Lu, Minmin ^{[3
,4
]}

Yi, Cuiying ^{[2
]}

Han, Gye Won ^{[8
]}

Wang, Xianping ^{[1
]}

Li, Xuemei ^{[1
]}

Yang, Huaiyu ^{[9
]}

Rao, Zihe ^{[1
]}

Jiang, Hualiang ^{[2
,3
,9
]}

Zhao, Yongfang ^{[1
]}

Liu, Jianfeng ^{[5
,6
]}

Stevens, Raymond C. ^{[10
,11
]}

Zhao, Qiang ^{[2
,3
,4
,12
]}

Zhang, Xuejun C. ^{[1
,4
]}

Wu, Beili ^{[2
,4
,11
,12
]}

机构：

[1] Chinese Acad Sci, Natl Ctr Prot Sci Beijing, Inst Biophys, Natl Lab Biomacromol,CAS Ctr Excellence Biomacrom, Beijing, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China

[4] Univ Chinese Acad Sci, Beijing, Peoples R China

[5] Huazhong Univ Sci & Technol, Minist Educ, Coll Life Sci & Technol, Collaborat Innovat Ctr Genet & Dev, Wuhan, Hubei, Peoples R China

[6] Huazhong Univ Sci & Technol, Minist Educ, Key Lab Mol Biophys, Wuhan, Hubei, Peoples R China

[7] Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, Zhengzhou, Henan, Peoples R China

[8] Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA USA

[9] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai, Peoples R China

[10] ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China

[11] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China

[12] Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Beijing, Peoples R China

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2018年 / 25卷 / 06期

基金：

美国国家科学基金会;

关键词：

PROTEIN-COUPLED-RECEPTOR; CRYO-EM STRUCTURE; HUMAN P2Y(12) RECEPTOR; CRYSTAL-STRUCTURE; FORCE-FIELD; CONFORMATIONAL-CHANGES; GLP-1; RECEPTOR; HIGHLY POTENT; COMPLEX; ANTAGONIST;

D O I：

10.1038/s41594-018-0068-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-A and 2.9-A 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 13A and 44, 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.

引用

页码：488 / +

页数：10

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