9WIK

Cryo-EM structure of GPR84-Gi complex with DL-175

This is a non-PDB format compatible entry.

Summary for 9WIK

• Entry DOI: 10.2210/pdb9wik/pdb
• EMDB information: 65999
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, signaling protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 193418.04

Authors

Suzuki, S.,Nishikawa, K.,Tran, D.P.,Akio, K.,Fujiyoshi, Y. (deposition date: 2025-08-28, release date: 2026-07-01, Last modification date: 2026-07-29)

Primary citation

Suzuki, S.,Tran, D.P.,Nishikawa, K.,Kitao, A.,Fujiyoshi, Y.
Mechanistic insight into signal bias by the agonist-dependent conformational dynamics of GPR84.
Nat Commun, 2026

PubMed 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 L336 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.

PubMed: 42463693
DOI: 10.1038/s41467-026-75728-9

Experimental method

ELECTRON MICROSCOPY (3.3 Å)