Mechanism of GPR84 allosteric modulation at a helix 8-proximate site.

A helix 8-proximate allosteric site in GPR84 enables G i-biased signaling, with PSB-16671 stabilizing a receptor conformation that favors G protein coupling over β-arrestin recruitment.

• Why it matters: Understanding how allosteric modulators induce biased signaling in GPCRs is crucial for developing pathway-selective therapies, yet the mechanisms remain unclear, limiting drug design.
• What they did: Cryo-electron microscopy, molecular dynamics simulations, and mutagenesis identified a specific allosteric site between TM1 and TM7 in GPR84, revealing how PSB-16671 influences receptor conformation and signaling bias.
• The result: This work uncovers a broadly targetable allosteric mechanism across class A GPCRs, enabling the design of biased modulators that can enhance therapeutic specificity and reduce side effects.