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The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)

The long-chain fatty acid receptor FFA4 (previously GPR120) is receiving substantial interest as a novel target for the treatment of metabolic and inflammatory disease. This study examines for the first time the detailed mode of binding of both long-chain fatty acid and synthetic agonist ligands at...

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Autores principales: Hudson, Brian D., Shimpukade, Bharat, Milligan, Graeme, Ulven, Trond
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106347/
https://www.ncbi.nlm.nih.gov/pubmed/24860101
http://dx.doi.org/10.1074/jbc.M114.561449
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author Hudson, Brian D.
Shimpukade, Bharat
Milligan, Graeme
Ulven, Trond
author_facet Hudson, Brian D.
Shimpukade, Bharat
Milligan, Graeme
Ulven, Trond
author_sort Hudson, Brian D.
collection PubMed
description The long-chain fatty acid receptor FFA4 (previously GPR120) is receiving substantial interest as a novel target for the treatment of metabolic and inflammatory disease. This study examines for the first time the detailed mode of binding of both long-chain fatty acid and synthetic agonist ligands at FFA4 by integrating molecular modeling, receptor mutagenesis, and ligand structure-activity relationship approaches in an iterative format. In doing so, residues required for binding of fatty acid and synthetic agonists to FFA4 have been identified. This has allowed for the refinement of a well validated model of the mode of ligand-FFA4 interaction that will be invaluable in the identification of novel ligands and the future development of this receptor as a therapeutic target. The model reliably predicted the effects of substituent variations on agonist potency, and it was also able to predict the qualitative effect of binding site mutations in the majority of cases.
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spelling pubmed-41063472014-07-23 The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120) Hudson, Brian D. Shimpukade, Bharat Milligan, Graeme Ulven, Trond J Biol Chem Signal Transduction The long-chain fatty acid receptor FFA4 (previously GPR120) is receiving substantial interest as a novel target for the treatment of metabolic and inflammatory disease. This study examines for the first time the detailed mode of binding of both long-chain fatty acid and synthetic agonist ligands at FFA4 by integrating molecular modeling, receptor mutagenesis, and ligand structure-activity relationship approaches in an iterative format. In doing so, residues required for binding of fatty acid and synthetic agonists to FFA4 have been identified. This has allowed for the refinement of a well validated model of the mode of ligand-FFA4 interaction that will be invaluable in the identification of novel ligands and the future development of this receptor as a therapeutic target. The model reliably predicted the effects of substituent variations on agonist potency, and it was also able to predict the qualitative effect of binding site mutations in the majority of cases. American Society for Biochemistry and Molecular Biology 2014-07-18 2014-05-24 /pmc/articles/PMC4106347/ /pubmed/24860101 http://dx.doi.org/10.1074/jbc.M114.561449 Text en © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles
spellingShingle Signal Transduction
Hudson, Brian D.
Shimpukade, Bharat
Milligan, Graeme
Ulven, Trond
The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)
title The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)
title_full The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)
title_fullStr The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)
title_full_unstemmed The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)
title_short The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)
title_sort molecular basis of ligand interaction at free fatty acid receptor 4 (ffa4/gpr120)
topic Signal Transduction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106347/
https://www.ncbi.nlm.nih.gov/pubmed/24860101
http://dx.doi.org/10.1074/jbc.M114.561449
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