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

Hudson, B. D. , Shimpukade, B., Milligan, G. and Ulven, T. (2014) The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120). Journal of Biological Chemistry, 289, pp. 20345-20358. (doi: 10.1074/jbc.M114.561449) (PMID:24860101) (PMCID:PMC4106347)

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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. The current study examines for the first time the detailed mode of binding of both a 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 which will be invaluable in the identification of novel ligands and future development of this receptor as a therapeutic target. The model reliably predicted the effects of substituent variations on agonist potency, and was also able to predict the qualitative effect of binding site mutations in the majority of cases.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Hudson, Dr Brian and Milligan, Professor Graeme
Authors: Hudson, B. D., Shimpukade, B., Milligan, G., and Ulven, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Journal of Biological Chemistry 289:20345-20358
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
618921GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammationGraeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/K019856/1RI MOLECULAR CELL & SYSTEMS BIOLOGY