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

Abstract

Background: FFA4 is a receptor for long-chain fatty acids and is considered a novel target for metabolic diseases.

Results: Combinations of molecular modeling, receptor mutagenesis, and ligand structure-activity relationships defined the binding pocket.

Conclusion: Fatty acid and synthetic agonists share an overlapping binding site.

Significance: The validated homology model will assist the search for novel ligands.

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.