8WW2

GPR3/Gs complex

Summary for 8WW2

• Entry DOI: 10.2210/pdb8ww2/pdb
• EMDB information: 37881
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, 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, ... (9 entities in total)
• Functional Keywords: gpcr-g-protein complex, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 141785.80

Authors

He, Y.,Xiong, Y. (deposition date: 2023-10-24, release date: 2024-02-14, Last modification date: 2025-07-02)

Primary citation

Xiong, Y.,Xu, Z.,Li, X.,Wang, Y.,Zhao, J.,Wang, N.,Duan, Y.,Xia, R.,Han, Z.,Qian, Y.,Liang, J.,Zhang, A.,Guo, C.,Inoue, A.,Xia, Y.,Chen, Z.,He, Y.
Identification of oleic acid as an endogenous ligand of GPR3.
Cell Res., 34:232-244, 2024

PubMed Abstract: Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by combining structural approach (including cryo-electron microscopy), mass spectrometry analysis, and functional studies, we identify oleic acid (OA) as an endogenous ligand of GPR3. Our study reveals a hydrophobic tunnel within GPR3 that connects the extracellular side of the receptor to the middle of plasma membrane, enabling fatty acids to readily engage the receptor. Functional studies demonstrate that OA triggers downstream G signaling, whereas lysophospholipids fail to activate the receptor. Moreover, our research reveals that cold stimulation induces the secretion of OA in mice, subsequently activating G/cAMP/PKA signaling in brown adipose tissue. Notably, brown adipose tissues from Gpr3 knockout mice do not respond to OA during cold stimulation, reinforcing the significance of GPR3 in this process. Finally, we propose a "born to be activated and cold to enhance" model for GPR3 activation. Our study provides a starting framework for the understanding of GPR3 signaling in cold-stimulated thermogenesis.

PubMed: 38287117
DOI: 10.1038/s41422-024-00932-5

Experimental method

ELECTRON MICROSCOPY (2.79 Å)