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

Can Cao; Qiuxiang Tan; Chanjuan Xu; Lingli He; Linlin Yang; Ye Zhou; Yiwei Zhou; Anna Qiao; Minmin Lu; Cuiying Yi; Gye Won Han; Xianping Wang; Xuemei Li; Huaiyu Yang; Zihe Rao; Hualiang Jiang; Yongfang Zhao; Jianfeng Liu; Raymond C. Stevens; Qiang Zhao; Xuejun C. Zhang; Beili Wu

doi:10.1038/s41594-018-0068-y

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

Can Cao, Qiuxiang Tan, Chanjuan Xu, Lingli He, Linlin Yang, Ye Zhou, Yiwei Zhou, Anna Qiao, Minmin Lu, Cuiying Yi, Gye Won Han, Xianping Wang, Xuemei Li, Huaiyu Yang, Zihe Rao, Hualiang Jiang, Yongfang Zhao, Jianfeng Liu, Raymond C. Stevens, Qiang ZhaoXuejun C. Zhang, Beili Wu

Research output: Contribution to journal › Article › peer-review

70 Scopus citations

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.

Original language	English
Pages (from-to)	488-495
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	25
Issue number	6
DOIs	https://doi.org/10.1038/s41594-018-0068-y
State	Published - 1 Jun 2018
Externally published	Yes

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Cao, C., Tan, Q., Xu, C., He, L., Yang, L., Zhou, Y., Zhou, Y., Qiao, A., Lu, M., Yi, C., Han, G. W., Wang, X., Li, X., Yang, H., Rao, Z., Jiang, H., Zhao, Y., Liu, J., Stevens, R. C., ... Wu, B. (2018). Structural basis for signal recognition and transduction by platelet-activating-factor receptor. Nature Structural and Molecular Biology, 25(6), 488-495. https://doi.org/10.1038/s41594-018-0068-y

@article{887a36eb37334ccb815b6454a5125b1d,

title = "Structural basis for signal recognition and transduction by platelet-activating-factor receptor",

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-{\AA} and 2.9-{\AA} 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 {\AA} and 4 {\AA}, 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.",

author = "Can Cao and Qiuxiang Tan and Chanjuan Xu and Lingli He and Linlin Yang and Ye Zhou and Yiwei Zhou and Anna Qiao and Minmin Lu and Cuiying Yi and Han, \{Gye Won\} and Xianping Wang and Xuemei Li and Huaiyu Yang and Zihe Rao and Hualiang Jiang and Yongfang Zhao and Jianfeng Liu and Stevens, \{Raymond C.\} and Qiang Zhao and Zhang, \{Xuejun C.\} and Beili Wu",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jun,

day = "1",

doi = "10.1038/s41594-018-0068-y",

language = "英语",

volume = "25",

pages = "488--495",

journal = "Nature Structural and Molecular Biology",

issn = "1545-9993",

publisher = "Nature Research",

number = "6",

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Cao, C, Tan, Q, Xu, C, He, L, Yang, L, Zhou, Y, Zhou, Y, Qiao, A, Lu, M, Yi, C, Han, GW, Wang, X, Li, X, Yang, H, Rao, Z, Jiang, H, Zhao, Y, Liu, J, Stevens, RC, Zhao, Q, Zhang, XC & Wu, B 2018, 'Structural basis for signal recognition and transduction by platelet-activating-factor receptor', Nature Structural and Molecular Biology, vol. 25, no. 6, pp. 488-495. https://doi.org/10.1038/s41594-018-0068-y

TY - JOUR

T1 - Structural basis for signal recognition and transduction by platelet-activating-factor receptor

AU - Cao, Can

AU - Tan, Qiuxiang

AU - Xu, Chanjuan

AU - He, Lingli

AU - Yang, Linlin

AU - Zhou, Ye

AU - Zhou, Yiwei

AU - Qiao, Anna

AU - Lu, Minmin

AU - Yi, Cuiying

AU - Han, Gye Won

AU - Wang, Xianping

AU - Li, Xuemei

AU - Yang, Huaiyu

AU - Rao, Zihe

AU - Jiang, Hualiang

AU - Zhao, Yongfang

AU - Liu, Jianfeng

AU - Stevens, Raymond C.

AU - Zhao, Qiang

AU - Zhang, Xuejun C.

AU - Wu, Beili

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85047830796

U2 - 10.1038/s41594-018-0068-y

DO - 10.1038/s41594-018-0068-y

M3 - 文章

C2 - 29808000

AN - SCOPUS:85047830796

SN - 1545-9993

VL - 25

SP - 488

EP - 495

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 6

ER -

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

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