The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120)

Brian D Hudson; Bharat Shimpukade; Graeme Milligan; Trond Ulven

doi:10.1074/jbc.M114.561449

The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120)

Brian D Hudson, Bharat Shimpukade, Graeme Milligan, Trond Ulven

45 Citationer (Scopus)

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Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Biological Chemistry
Vol/bind	289
Udgave nummer	29
Sider (fra-til)	20345-20358
Antal sider	14
ISSN	0021-9258
DOI	https://doi.org/10.1074/jbc.M114.561449
Status	Udgivet - 18 jul. 2014
Udgivet eksternt	Ja

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10.1074/jbc.M114.561449Licens: CC BY

J. Biol. Chem.-2014-Hudson-20345-58Licens: CC BY

Citationsformater

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The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120)

Abstract

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