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TitleMolecular basis for the activation of PAF receptor by PAF.
Journal, issue, pagesCell Rep, Vol. 43, Issue 7, Page 114422, Year 2024
Publish dateJul 23, 2024
AuthorsWenjia 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 /
PubMed AbstractPlatelet-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 ...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 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.
External linksCell Rep / PubMed:38943642
MethodsEM (single particle)
Resolution2.9 Å
Structure data

38769

8xyd

EMDB-38769, PDB-8xyd:
Structure of Platelet-activating factor receptor-G protein complex bound to platelet-activating factor
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-PFS:
(2R)-2-(acetyloxy)-3-(hexadecyloxy)propyl 2-(trimethylammonio)ethyl phosphate

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / PTAFR

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