ArticleMolecular pharmacology2012
Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor.
Article in Molecular pharmacology, 2012. 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, 119 citations in OpenAlex.
- Dietary tributyrin supplementation in Parkinson's disease: An open-label target engagement study.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Multicolored sequential resonance energy transfer for detection of simultaneous ligand binding at G protein-coupled receptors.Nature communications · 2025Article
- A non-canonical mechanism of GPCR activation.Nature communications · 2024Article
- Molecular mechanism of fatty acid activation of FFAR1.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors.International journal of molecular sciences · 2022Review
- The epoxy fatty acid pathway enhances cAMP in mammalian cells through multiple mechanisms.Prostaglandins & other lipid mediators · 2022Article
- Mechanistic Studies on the Stereoselectivity of FFAR1 Modulators.Journal of chemical information and modeling · 2022Article
- Blood-Brain Barrier Disruption Mediated by FFA1 Receptor-Evidence Using Miniscope.International journal of molecular sciences · 2022Article
- A FFAR1 full agonist restores islet function in models of impaired glucose-stimulated insulin secretion and diabetic non-human primates.Frontiers in endocrinology · 2022Article
- Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders.Frontiers in pharmacology · 2022Review
- Lipid-Induced Adaptations of the Pancreatic Beta-Cell to Glucotoxic Conditions Sustain Insulin Secretion.International journal of molecular sciences · 2021Review
- Free fatty acid receptor 1: a ray of hope in the therapy of type 2 diabetes mellitus.Inflammopharmacology · 2021Review
- Olive Oil Lipophenols Induce Insulin Secretion in 832/13 β-Cell Models.Pharmaceutics · 2021Article
- Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges.Nature reviews. Endocrinology · 2021Review
- Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators.International journal of molecular sciences · 2021Review
- Insights into the molecular mechanism of positive cooperativity between partial agonist MK-8666 and full allosteric agonist AP8 of hGPR40 by Gaussian accelerated molecular dynamics (GaMD) simulations.Computational and structural biotechnology journal · 2021Article
- Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors.Frontiers in physiology · 2021Review
- Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics.Journal of computer-aided molecular design · 2020Article
- Leveraging the Gut to Treat Metabolic Disease.Cell metabolism · 2020Review
- Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.
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