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Molecular basis for the activation of PAF receptor by PAF.
Fan, Wenjia; Xu, Youwei; He, Xinheng; Luo, Ping; Zhu, Jingpeng; Li, Junrui; Wang, Ruolan; Yuan, Qingning; Wu, Kai; Hu, Wen; Zhao, Yuxi; Xu, Shiqi; Cheng, Xi; Wang, Yue; Xu, H Eric; Zhuang, Youwen.
  • Fan W; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Xu Y; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • He X; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Luo P; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhu J; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Li J; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Wang R; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Yuan Q; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Wu K; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Hu W; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Zhao Y; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Xu S; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Cheng X; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Wang Y; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: wangyue1@simm.ac.cn.
  • Xu HE; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Ele
  • Zhuang Y; The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Medicinal Bioinformatics Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address: youwen_zhuang@sjtu.edu.cn.
Cell Rep ; 43(7): 114422, 2024 Jul 23.
Article en En | MEDLINE | ID: mdl-38943642
ABSTRACT
Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-Gi complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Factor de Activación Plaquetaria / Glicoproteínas de Membrana Plaquetaria / Receptores Acoplados a Proteínas G Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Factor de Activación Plaquetaria / Glicoproteínas de Membrana Plaquetaria / Receptores Acoplados a Proteínas G Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article