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<p>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 L336<sup>6.52</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月16日

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  • Shota Suzuki,
  • Duy Phuoc Tran,
  • Kouki Nishikawa,
  • Akio Kitao,
  • Yoshinori Fujiyoshi

摘要

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.