8J18

Cryo-EM structure of the 3-OH-C12-bound GPR84 receptor-Gi complex

Summary for 8J18

• Entry DOI: 10.2210/pdb8j18/pdb
• Related: 8J19 8J1A
• EMDB information: 35913 35914 35915
• 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, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 160585.69

Authors

Liu, H.,Yin, W.,Xu, H.E. (deposition date: 2023-04-12, release date: 2023-06-21, Last modification date: 2024-10-23)

Primary citation

Liu, H.,Zhang, Q.,He, X.,Jiang, M.,Wang, S.,Yan, X.,Cheng, X.,Liu, Y.,Nan, F.J.,Xu, H.E.,Xie, X.,Yin, W.
Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84.
Nat Commun, 14:3271-3271, 2023

PubMed Abstract: GPR84 is an orphan class A G protein-coupled receptor (GPCR) that is predominantly expressed in immune cells and plays important roles in inflammation, fibrosis, and metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of Gα protein-coupled human GPR84 bound to a synthetic lipid-mimetic ligand, LY237, or a putative endogenous ligand, a medium-chain fatty acid (MCFA) 3-hydroxy lauric acid (3-OH-C12). Analysis of these two ligand-bound structures reveals a unique hydrophobic nonane tail -contacting patch, which forms a blocking wall to select MCFA-like agonists with the correct length. We also identify the structural features in GPR84 that coordinate the polar ends of LY237 and 3-OH-C12, including the interactions with the positively charged side chain of R172 and the downward movement of the extracellular loop 2 (ECL2). Together with molecular dynamics simulations and functional data, our structures reveal that ECL2 not only contributes to direct ligand binding, but also plays a pivotal role in ligand entry from the extracellular milieu. These insights into the structure and function of GPR84 could improve our understanding of ligand recognition, receptor activation, and Gα-coupling of GPR84. Our structures could also facilitate rational drug discovery against inflammation and metabolic disorders targeting GPR84.

PubMed: 37277332
DOI: 10.1038/s41467-023-38985-6

Experimental method

ELECTRON MICROSCOPY (2.89 Å)