Mechanistic insight into signal bias by the agonist-dependent conformational dynamics of GPR84

GPR84 is an orphan class A GPCR primarily expressed in immune cells, where it plays key roles in inflammation and metabolism. Here, we present the cryo-electron microscopy structures of the GPR84-Gi complex bound to the G protein–biased agonist DL-175, and the inactive state of GPR84 bound to the antagonist GLPG1205. Combined with signaling assays and molecular dynamics simulations, these structures elucidate the conformational landscape spanning the inactive and G protein-biased active states of GPR84, providing a mechanistic basis for biased agonism. Notably, steric interactions between DL-175 and L3366.52 selectively preclude the conformational changes required for efficient β-arrestin recruitment without compromising G protein activation. These structural insights provide a structural context for the rational design of GPR84-targeted therapeutics with precisely tuned signaling profiles. Authors here solve cryo-EM structures of the immune receptor GPR84, which reveal how a ‘biased’ drug favors one signaling pathway over another. A single steric clash inside the receptor acts as the switch, guiding the design of safer, more selective drugs.