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Updated: Aug 6, 2026

Quantifying Agonist Activity at G Protein-coupled Receptors
Published on: December 26, 2011
Mechanistic insight into signal bias by the agonist-dependent conformational dynamics of GPR84
Shota Suzuki1, Duy Phuoc Tran2, Kouki Nishikawa3
1Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan. sshota.cesp@tmd.ac.jp.
Abstract:
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.
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