Pro-phagocytic function and structural basis of GPR84 signaling

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.