ArticleThe Journal of biological chemistry2013
Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 123 citations in OpenAlex.
- Short-chain fatty acids promote post-myocardial infarction cardiac repair via FFAR2-dependent suppression of osteoclast-like macrophage differentiation.Basic research in cardiology · 2026Article
- Free fatty acid receptor 2 allosterism is defined by cellular context.Cell communication and signaling : CCS · 2026Article
- Structural insights into lipid chain-length selectivity and allosteric regulation of FFA2.Nature communications · 2025Article
- Development of a yeast-based sensor platform for evaluation of ligands recognized by the human free fatty acid 2 receptor.FEMS yeast research · 2025Article
- Free Fatty Acids and Free Fatty Acid Receptors: Role in Regulating Arterial Function.International journal of molecular sciences · 2024Review
- Sensing of luminal contents and downstream modulation of GI function.JGH open : an open access journal of gastroenterology and hepatology · 2024Review
- [Research progress in the regulation of pathogenesis and the transformation of chronic liver disease by short-chain fatty acids].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2024Review
- Structural basis for the ligand recognition and signaling of free fatty acid receptors.Science advances · 2024Article
- Phosphorylation bar-coding of free fatty acid receptor 2 is generated in a tissue-specific manner.eLife · 2023Article
- Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists.Journal of medicinal chemistry · 2023Article
- The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs.PloS one · 2023Article
- Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease.Frontiers in endocrinology · 2023Review
- GPCR-mediated effects of fatty acids and bile acids on glucose homeostasis.Frontiers in endocrinology · 2023Review
- Mechanisms of Short-Chain Fatty Acids Derived from Gut Microbiota in Alzheimer's Disease.Aging and disease · 2022Review
- Identifying predictive signalling networks for Vedolizumab response in ulcerative colitis.International journal of colorectal disease · 2022Article
- Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook.Cells · 2022Review
- Metabolic responses of light and taste receptors - unexpected actions of GPCRs in adipocytes.Reviews in endocrine & metabolic disorders · 2022Review
- Dietary fatty acids in gut health: Absorption, metabolism and function.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2021Review
- Activation of Free Fatty Acid Receptor 4 Affects Intestinal Inflammation and Improves Colon Permeability in Mice.Nutrients · 2021Article
- Review
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
FFA2 is a G protein-coupled receptor that responds to short chain fatty acids and has generated interest as a therapeutic target for metabolic and inflammatory conditions. However, definition of its functions has been slowed by a dearth of selective ligands that can distinguish it from the closely related FFA3. At present, the only selective ligands described for FFA2 suffer from poor potency, altered signaling due to allosteric modes of action, or a lack of function at non-human orthologs of the receptor. To address the need for novel selective ligands, we synthesized two compounds potentially having FFA2 activity and examined the molecular basis of their function. These compounds were confirmed to be potent and selective orthosteric FFA2 agonists. A combination of ligand structure-activity relationship, pharmacological analysis, homology modeling, species ortholog comparisons, and mutagenesis studies were then employed to define the molecular basis of selectivity and function of these ligands. From this, we identified key residues within both extracellular loop 2 and the transmembrane domain regions of FFA2 critical for ligand function. One of these ligands was active with reasonable potency at rodent orthologs of FFA2 and demonstrated the role of FFA2 in inhibition of lipolysis and glucagon-like peptide-1 secretion in murine-derived 3T3-L1 and STC-1 cell lines, respectively. Together, these findings describe the first potent and selective FFA2 orthosteric agonists and demonstrate key aspects of ligand interaction within the binding site of FFA2 that will be invaluable in future ligand development at this receptor.
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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.