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TitlePro-phagocytic function and structural basis of GPR84 signaling.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 5706, Year 2023
Publish dateSep 14, 2023
AuthorsXuan Zhang / Yujing Wang / Shreyas Supekar / Xu Cao / Jingkai Zhou / Jessica Dang / Siqi Chen / Laura Jenkins / Sara Marsango / Xiu Li / Guibing Liu / Graeme Milligan / Mingye Feng / Hao Fan / Weimin Gong / Cheng Zhang /
PubMed AbstractGPR84 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 ...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.
External linksNat Commun / PubMed:37709767 / PubMed Central
MethodsEM (single particle)
Resolution3.0 Å
Structure data

29645

8g05

EMDB-29645, PDB-8g05:
Cryo-EM structure of an orphan GPCR-Gi protein signaling complex
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-YI9:
6-(octylamino)pyrimidine-2,4(3H,5H)-dione

ChemComp-CLR:
CHOLESTEROL

Source
  • Spodoptera frugiperda (fall armyworm)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCR / agonist / 6-OAU

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