Molecular basis for the activation of PAF receptor by PAF

Wenjia Fan; Youwei Xu; Xinheng He; Ping Luo; Jingpeng Zhu; Junrui Li; Ruolan Wang; Qingning Yuan; Kai Wu; Wen Hu; Yuxi Zhao; Shiqi Xu; Xi Cheng; Yue Wang; H Eric Xu; Youwen Zhuang

doi:10.1016/j.celrep.2024.114422

Molecular basis for the activation of PAF receptor by PAF

Cell Rep. 2024 Jul 23;43(7):114422. doi: 10.1016/j.celrep.2024.114422. Epub 2024 Jun 28.

Authors

Wenjia Fan¹, Youwei Xu², Xinheng He³, Ping Luo², Jingpeng Zhu², Junrui Li², Ruolan Wang³, Qingning Yuan⁴, Kai Wu⁴, Wen Hu⁴, Yuxi Zhao¹, Shiqi Xu², Xi Cheng³, Yue Wang⁵, H Eric Xu⁶, Youwen Zhuang⁷

Affiliations

¹ 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.
² The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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. Electronic address: eric.xu@simm.ac.cn.
⁷ 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.

PMID: 38943642
DOI: 10.1016/j.celrep.2024.114422

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-G_i 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.

Keywords: CP: Molecular biology; GPCR; PAFR; activation mechanism; cryo-EM; inflammation; ligand binding; platelet-activating factor; signaling complex.

MeSH terms

Binding Sites
HEK293 Cells
Humans
Molecular Dynamics Simulation
Platelet Activating Factor* / metabolism
Platelet Membrane Glycoproteins* / chemistry
Platelet Membrane Glycoproteins* / metabolism
Protein Binding
Receptors, G-Protein-Coupled* / chemistry
Receptors, G-Protein-Coupled* / metabolism
Signal Transduction

Substances

Platelet Membrane Glycoproteins
platelet activating factor receptor
Platelet Activating Factor
Receptors, G-Protein-Coupled