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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2014
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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. |
format | Online Article Text |
id | pubmed-4106347 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
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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