In:
Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6640 ( 2023-04-07)
Abstract:
Hormones regulate most aspects of human physiology and are generally divided into four groups: protein and peptides, monoamines, steroids, and free fatty acids (FAs). Unsaturated FAs, those with C–C double bonds, exert physiological functions through engagement with membrane receptors, many of which are G protein–coupled receptors (GPCRs). Omega-3 (ω-3) FAs, which are a main component of fish oil, bind to the receptor GPR120, which mediates insulin sensitization, stimulates glucagon-like peptide 1 (GLP-1) secretion, and controls adipogenesis and anti-inflammatory effects through coupling to distinct downstream effectors, including the guanine nucleotide–binding (G) proteins G s , G i , and G q and β-arrestins. The association of the p.R270H missense mutation of GPR120 in obesity suggests therapeutic potential for GPR120 in the treatment of metabolic diseases. RATIONALE How natural fatty acid hormones—which are amphipathic molecules, distinguished mainly by number and position of double bonds—interact with GPCRs such as GPR120 has been unclear. Both saturated and unsaturated FAs are able to activate GPR120, but only certain unsaturated FAs are beneficial for metabolism. It is therefore important to understand whether GPR120 can recognize selective double-bond decorations in FAs and, if so, translate binding to specific biological signaling pathways, including different G protein subtypes and arrestins. The lack of GPCR structures in complex with natural fatty acid hormones and downstream effectors has hampered our understanding of double-bond recognition, which is one challenge in developing therapeutics that might act through this receptor. RESULTS By profiling G protein and arrestin activities of GPR120 stimulated by saturated and unsaturated endogenous FAs or the synthetic compound TUG891, we found that these molecules exhibited different biased signaling properties. In particular, only the beneficial ω-3 FAs were able to activate G s signaling. We determined six cryo–electron microscopy (cryo-EM) structures of GPR120-G i /G iq with 9-hydroxystearic acid (9-HSA), linoleic acid (LA), oleic acid (OA), the natural agonist ω-3 eicosapentaenoic acid (EPA), and the synthetic agonist TUG891. All fatty acid hormones and TUG891 assumed an overall “L” configuration and were buried inside the seven-transmembrane (7TM) helix bundle of the receptor. Through structural and mutational analysis, biochemical characterization, and molecular simulations, we identified aromatic residues in the ligand pocket of GPR120 that specifically recognize the C–C double bonds present in unsaturated FAs through π:π interactions and translate this recognition into different signaling outcomes. A propagating path connects the double-bond recognition of GPR120 inside the ligand pocket of the cytoplasmic side, and common and distinct features of G s and G q coupling interfaces were investigated. We also analyzed the structural basis for selectivity of TUG891 toward GPR120 and a disease-associated single-nucleotide polymorphism of GPR120. The separation of TUG891 into two regions by a linker oxygen suggests that fragment-based drug design could be exploited for GPR120 ligand design. CONCLUSION Our cryo-EM structures reveal how fatty acid hormones bind the orthosteric site within the 7TM domain of GPCRs and how specific aromatic residues inside the ligand pocket recognize the C–C double bonds. We also investigated mechanisms underlying signaling bias of GPR120 in response to various ligands. This work will serve as a foundation for the development of molecules that bind and activate GPR120 for potential therapeutic uses as well as to better understand how ligand-induced conformational changes bias signaling outcomes in GPRCs. Fish oil membrane receptor GPR120 recognizes different unsaturated FAs and couples to distinct downstream effectors. The membrane receptor GPR120 specifically recognizes the C–C double bonds present in unsaturated FAs, such as those in the ω-3 FAs found in fish oil, through π:π interactions. The interaction patterns of different FAs or ligands inside of the ligand pocket of GPR120 are translated into different signaling outcomes via distinct propagating paths. GLUT4, glucose transporter member 4; cAMP, cyclic adenosine monophosphate; TAK1, transforming growth factor-β–activated kinase 1; NLRP3, NLR family pyrin domain containing 3.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.add6220
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2023
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128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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