ArticleThe Journal of biological chemistry2011
Selective orthosteric free fatty acid receptor 2 (FFA2) agonists: identification of the structural and chemical requirements for selective activation of FFA2 versus FFA3.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 122 citations in OpenAlex.
- Trifluoroacetate mediated reduction of atherosclerosis in mice.Nature communications · 2026Article
- Short-chain fatty acids.Nature metabolism · 2026Review
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Review
- Short-Chain Fatty Acids Activate Myenteric Neurons and Delay Colonic Motility via Free Fatty Acid Receptors 2 and 3 in the Mouse.Neurogastroenterology and motility · 2026Article
- Development of a yeast-based sensor platform for evaluation of ligands recognized by the human free fatty acid 2 receptor.FEMS yeast research · 2025Article
- Endogenous ligands of bovine FFAR2/GPR43 display distinct pharmacological properties.Frontiers in cell and developmental biology · 2025Article
- Microbial metabolite-receptor interactions in the gut microbiome.Current opinion in chemical biology · 2024Review
- Intestinal FFA2 promotes obesity by altering food intake in Western diet-fed mice.The Journal of endocrinology · 2024Article
- Effects of Ecologically Relevant Concentrations of Cadmium on the Microbiota, Short-Chain Fatty Acids, and FFARMetabolites · 2023Article
- Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists.Journal of medicinal chemistry · 2023Article
- Short-chain fatty acids: possible regulators of insulin secretion.Molecular and cellular biochemistry · 2023Review
- Analysis of microbiota-host communication mediated by butyrate in Atlantic salmon.Computational and structural biotechnology journal · 2023Article
- Bone loss is ameliorated by fecal microbiota transplantation through SCFA/GPR41/ IGF1 pathway in sickle cell disease mice.Scientific reports · 2022Article
- A Dynamic Mass Redistribution Assay for the Human Sweet Taste Receptor Uncovers G-Protein Dependent Biased Ligands.Frontiers in pharmacology · 2022Article
- Review
- Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators.International journal of molecular sciences · 2021Review
- Metabolic and inflammatory functions of short-chain fatty acid receptors.Current opinion in endocrine and metabolic research · 2021Review
- Gut microbiota-derived propionate mediates the neuroprotective effect of osteocalcin in a mouse model of Parkinson's disease.Microbiome · 2021Article
- Free Fatty Acid Receptors as Mediators and Therapeutic Targets in Liver Disease.Frontiers in physiology · 2021Review
- Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer.Frontiers in physiology · 2021Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Free fatty acid receptor 2 (FFA2; GPR43) is a G protein-coupled seven-transmembrane receptor for short-chain fatty acids (SCFAs) that is implicated in inflammatory and metabolic disorders. The SCFA propionate has close to optimal ligand efficiency for FFA2 and can hence be considered as highly potent given its size. Propionate, however, does not discriminate between FFA2 and the closely related receptor FFA3 (GPR41). To identify FFA2-selective ligands and understand the molecular basis for FFA2 selectivity, a targeted library of small carboxylic acids was examined using holistic, label-free dynamic mass redistribution technology for primary screening and the receptor-proximal G protein [(35)S]guanosine 5'-(3-O-thio)triphosphate activation, inositol phosphate, and cAMP accumulation assays for hit confirmation. Structure-activity relationship analysis allowed formulation of a general rule to predict selectivity for small carboxylic acids at the orthosteric binding site where ligands with substituted sp(3)-hybridized α-carbons preferentially activate FFA3, whereas ligands with sp(2)- or sp-hybridized α-carbons prefer FFA2. The orthosteric binding mode was verified by site-directed mutagenesis: replacement of orthosteric site arginine residues by alanine in FFA2 prevented ligand binding, and molecular modeling predicted the detailed mode of binding. Based on this, selective mutation of three residues to their non-conserved counterparts in FFA3 was sufficient to transfer FFA3 selectivity to FFA2. Thus, selective activation of FFA2 via the orthosteric site is achievable with rather small ligands, a finding with significant implications for the rational design of therapeutic compounds selectively targeting the SCFA receptors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.