ArticleThe Journal of biological chemistry2009
Two arginine-glutamate ionic locks near the extracellular surface of FFAR1 gate receptor activation.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 58 citations in OpenAlex.
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- Molecular mechanism of fatty acid activation of FFAR1.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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- Insight into Gentisic Acid Antidiabetic Potential Using In Vitro and In Silico Approaches.Molecules (Basel, Switzerland) · 2021Article
- Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators.International journal of molecular sciences · 2021Review
- Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics.Journal of computer-aided molecular design · 2020Article
- In-Vivo Antidiabetic Activity and In-Silico Mode of Action of LC/MS-MS Identified Flavonoids in Oleaster Leaves.Molecules (Basel, Switzerland) · 2020Article
- Review
- Free fatty acid receptors: structural models and elucidation of ligand binding interactions.BMC structural biology · 2015Article
- Model structures of inactive and peptide agonist bound C5aR: Insights into agonist binding, selectivity and activation.Biochemistry and biophysics reports · 2015Article
- Article
- High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875.Nature · 2014Article
- Novel insights on thyroid-stimulating hormone receptor signal transduction.Endocrine reviews · 2013Review
- Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor.The Journal of biological chemistry · 2013Article
- A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1.PloS one · 2013Article
- Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3.The Journal of biological chemistry · 2012Article
- Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor.Molecular pharmacology · 2012Article
- Comparison of dynamics of extracellular accesses to the β(1) and β(2) adrenoceptors binding sites uncovers the potential of kinetic basis of antagonist selectivity.Chemical biology & drug design · 2012Article
- Lifting the lid on GPCRs: the role of extracellular loops.British journal of pharmacology · 2012Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Activation of a number of class A G protein-coupled receptors (GPCRs) is thought to involve two molecular switches, a rotamer toggle switch within the transmembrane domain and an ionic lock at the cytoplasmic surface of the receptor; however, the mechanism by which agonist binding changes these molecular interactions is not understood. Importantly, 80% of GPCRs including free fatty acid receptor 1 (FFAR1) lack the complement of amino acid residues implicated in either or both of these two switches; the mechanism of activation of these GPCRs is therefore less clear. By homology modeling, we identified two Glu residues (Glu-145 and Glu-172) in the second extracellular loop of FFAR1 that form putative interactions individually with two transmembrane Arg residues (Arg-183(5.39) and Arg-258(7.35)) to create two ionic locks. Molecular dynamics simulations showed that binding of agonists to FFAR1 leads to breakage of these Glu-Arg interactions. In mutagenesis experiments, breakage of these two putative interactions by substituting Ala for Glu-145 and Glu-172 caused constitutive receptor activation. Our results therefore reveal a molecular switch for receptor activation present on the extracellular surface of FFAR1 that is broken by agonist binding. Similar ionic locks between the transmembrane domains and the extracellular loops may constitute a mechanism common to other class A GPCRs also.
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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.