Unsaturated bond recognition leads to biased signal in a fatty acid receptor
Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein–coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metaboli...
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| Published in | Science (American Association for the Advancement of Science) Vol. 380; no. 6640; p. eadd6220 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
07.04.2023
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0036-8075 1095-9203 1095-9203 |
| DOI | 10.1126/science.add6220 |
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| Abstract | Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein–coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo–electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G
i
or G
iq
trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.
In addition to being an energy source, fatty acids influence cells through their effects on membrane structure and as signaling molecules or precursors to signaling molecules. The G protein–coupled receptor GPR120 binds to various fatty acids, in particular polyunsaturated omega-3 fatty acids, which are essential components of the human diet. Mao
et al
. determined cryo–electron microscopy structures of GPR120–G protein complexes bound to natural lipids or a synthetic agonist and, in parallel, performed biochemical experiments to study biased signaling properties of the receptor. The tight binding pocket packs around the lipids, and hydrophobic and aromatic residues read out different double bonds, resulting in subtle structural changes that result in different activation and bias patterns for different ligands. These insights will be invaluable for efforts to target this receptor for drugs that treat metabolic and immune diseases. —MAF
Structures and biochemistry reveal how free fatty acid receptors recognize and respond to agonists. |
|---|---|
| AbstractList | Accounting for omega-3 double bondsIn addition to being an energy source, fatty acids influence cells through their effects on membrane structure and as signaling molecules or precursors to signaling molecules. The G protein–coupled receptor GPR120 binds to various fatty acids, in particular polyunsaturated omega-3 fatty acids, which are essential components of the human diet. Mao et al. determined cryo–electron microscopy structures of GPR120–G protein complexes bound to natural lipids or a synthetic agonist and, in parallel, performed biochemical experiments to study biased signaling properties of the receptor. The tight binding pocket packs around the lipids, and hydrophobic and aromatic residues read out different double bonds, resulting in subtle structural changes that result in different activation and bias patterns for different ligands. These insights will be invaluable for efforts to target this receptor for drugs that treat metabolic and immune diseases. —MAFINTRODUCTIONHormones 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 Gs, Gi, and Gq 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.RATIONALEHow 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.RESULTSBy 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 Gs signaling. We determined six cryo–electron microscopy (cryo-EM) structures of GPR120-Gi/Giq 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 Gs and Gq 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.CONCLUSIONOur 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. Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G or G trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120. Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and Gi or Giq trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and Gi or Giq trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120. Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein–coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo–electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G i or G iq trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120. In addition to being an energy source, fatty acids influence cells through their effects on membrane structure and as signaling molecules or precursors to signaling molecules. The G protein–coupled receptor GPR120 binds to various fatty acids, in particular polyunsaturated omega-3 fatty acids, which are essential components of the human diet. Mao et al . determined cryo–electron microscopy structures of GPR120–G protein complexes bound to natural lipids or a synthetic agonist and, in parallel, performed biochemical experiments to study biased signaling properties of the receptor. The tight binding pocket packs around the lipids, and hydrophobic and aromatic residues read out different double bonds, resulting in subtle structural changes that result in different activation and bias patterns for different ligands. These insights will be invaluable for efforts to target this receptor for drugs that treat metabolic and immune diseases. —MAF Structures and biochemistry reveal how free fatty acid receptors recognize and respond to agonists. |
| Author | Zhang, Dao-Lai Zhang, Cheng Mao, Chunyou Xu, H. Eric Huang, Shen-Ming Wang, Qian-Lang Cheng, Jie Liu, Mei-Xia He, Yong-Hao Zhang, Yan Qin, Jiao Guo, Yongyuan Li, Guo-Yu Wang, Chuanxin Feng, Shiqing Tao, Xiao-Na Zhong, Ya-Ni Guo, Sheng-Chao Chen, Jun Shen, Dan-Dan Yu, Xiao Sun, Jin-Peng Xiao, Peng He, Qing-Tao Zhang, Chao Du, Ya-Qin Yang, Zhi-Shuai Chen, Li-Nan Zhang, Han-Qiong Shang, Pan |
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| Snippet | Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein–coupled receptors.... Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors.... Accounting for omega-3 double bondsIn addition to being an energy source, fatty acids influence cells through their effects on membrane structure and as... |
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| SubjectTerms | Adipogenesis Agonists Arrestin Bias Binding Biphenyl Compounds - chemistry Biphenyl Compounds - pharmacology Coupling (molecular) Cryoelectron Microscopy Drug Design Drug development Effectors Eicosapentaenoic acid Eicosapentaenoic Acid - chemistry Eicosapentaenoic Acid - metabolism Electron microscopy Energy sources Fatty acids Fatty Acids, Omega-3 - chemistry Fatty Acids, Omega-3 - metabolism Fish oils G protein-coupled receptors Glucagon Glucagon-like peptide 1 Hormones Humans Hydrophobicity Immunological diseases Immunosuppressive agents Inflammation Interfaces Ligands Linoleic acid Lipids Membrane structure Membrane structures Membranes Metabolic disorders Metabolism Microscopy Missense mutation Molecular structure Monoamines Mutation, Missense Nucleotides Obesity Oleic acid Omega-3 fatty acids Peptides Phenylpropionates - chemistry Phenylpropionates - pharmacology Physiology Polymorphism Polymorphism, Single Nucleotide Protein Conformation Proteins Receptors Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - genetics Recognition Residues Signaling Steroid hormones Transmission electron microscopy |
| Title | Unsaturated bond recognition leads to biased signal in a fatty acid receptor |
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