Pro-phagocytic function and structural basis of GPR84 signaling

Area of Science:

• Immunology
• Structural Biology
• Pharmacology

Background:

• GPR84 is a G protein-coupled receptor (GPCR) activated by medium-chain fatty acids (MCFAs).
• GPR84 signaling is primarily pro-inflammatory and promotes macrophage phagocytosis.
• Targeting GPR84 presents a potential strategy for cancer immunotherapy.

Purpose of the Study:

• To investigate the synergistic effect of GPR84 activation and CD47 blockade on cancer cell phagocytosis.
• To determine the high-resolution structure of the GPR84-G_i signaling complex.
• To elucidate the molecular mechanisms underlying GPR84 activation, ligand binding, and selectivity.

Main Methods:

• Utilized a synthetic GPR84 agonist (6-OAU) and CD47 blockade in cancer cell-macrophage co-cultures.
• Determined the crystal structure of the GPR84-G_i signaling complex.
• Performed computational docking and molecular simulations.

Main Results:

• GPR84 activation synergizes with CD47 blockade to enhance macrophage-mediated cancer cell phagocytosis.
• The determined structure reveals an occluded 6-OAU binding pocket and an unusual G_i-coupling interface.
• Structural and computational data suggest mechanisms for MCFA selectivity and ligand interaction with GPR84.

Conclusions:

• GPR84 plays a significant role in modulating macrophage phagocytic activity against cancer cells.
• The high-resolution structure provides critical insights into GPR84 activation and signaling pathways.
• This research lays the groundwork for developing novel GPR84-targeted therapeutics for cancer treatment.