Related Experiment Video

Updated: Aug 9, 2025

A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors

Published on: June 8, 2022

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Pro-phagocytic function and structural basis of GPR84 signaling

Xuan Zhang1,2, Yujing Wang1, Shreyas Supekar3

  • 1Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Research Square
|February 24, 2023
PubMed

Insights

GPR84 receptor activation by 6-OAU enhances cancer cell phagocytosis, especially when combined with CD47 blockade. This study reveals the GPR84-Gi complex structure, aiding drug development for inflammatory diseases.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • G protein-coupled receptor 84 (GPR84) is a pro-inflammatory and pro-phagocytic receptor activated by medium-chain fatty acids (MCFAs).
  • Understanding GPR84's structure and signaling is crucial for developing targeted therapies for inflammatory conditions and cancer.

Approach:

  • Investigated the synergistic effect of GPR84 activation (using synthetic agonist 6-OAU) and CD47 blockade on cancer cell phagocytosis by macrophages.
  • Determined the high-resolution crystal structure of the GPR84-Gi signaling complex bound to 6-OAU.
  • Utilized computational docking and simulations to elucidate ligand binding mechanisms and receptor selectivity.

Key Points:

  • GPR84 activation synergizes with CD47 blockade to promote cancer cell phagocytosis.
  • The determined GPR84-Gi complex structure reveals an occluded ligand-binding pocket and an unusual Gi-coupling interface.
  • Structural and computational analyses suggest mechanisms for GPR84's MCFA selectivity and ligand interaction.

Conclusions:

  • The study provides a structural framework for understanding GPR84 signaling pathways.
  • Findings pave the way for the rational design of novel therapeutics targeting GPR84 for immune modulation and cancer treatment.

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