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

TY - JOUR

T1 - The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120)

AU - Hudson, Brian D

AU - Shimpukade, Bharat

AU - Milligan, Graeme

AU - Ulven, Trond

N1 - © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2014/7/18

Y1 - 2014/7/18

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M114.561449

DO - 10.1074/jbc.M114.561449

M3 - Journal article

SN - 0021-9258

VL - 289

SP - 20345

EP - 20358

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 29

ER -