8G05

Cryo-EM structure of an orphan GPCR-Gi protein signaling complex

Summary for 8G05

• Entry DOI: 10.2210/pdb8g05/pdb
• EMDB information: 29645
• Descriptor: G-protein coupled receptor 84, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (7 entities in total)
• Functional Keywords: gpcr, agonist, 6-oau, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 167141.46

Authors

Zhang, X.,Wang, Y.J.,Li, X.,Liu, G.B.,Gong, W.M.,Zhang, C. (deposition date: 2023-01-31, release date: 2023-11-01, Last modification date: 2024-11-06)

Primary citation

Zhang, X.,Wang, Y.,Supekar, S.,Cao, X.,Zhou, J.,Dang, J.,Chen, S.,Jenkins, L.,Marsango, S.,Li, X.,Liu, G.,Milligan, G.,Feng, M.,Fan, H.,Gong, W.,Zhang, C.
Pro-phagocytic function and structural basis of GPR84 signaling.
Nat Commun, 14:5706-5706, 2023

PubMed Abstract: GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-G signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual G-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.

PubMed: 37709767
DOI: 10.1038/s41467-023-41201-0

Experimental method

ELECTRON MICROSCOPY (3 Å)