title: The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120).
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.
authors.affiliation: From the Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hudson
authors.affiliation: the Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: Bharat
authors.initials: B
authors.lastname: Shimpukade
authors.affiliation: From the Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom and Graeme.Milligan@glasgow.ac.uk.
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.affiliation: the Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark ulven@sdu.dk.
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
mesh_terms: D019943:Amino Acid Substitution; D019390:Arrestins / Q000378:metabolism; D001665:Binding Sites; D005230:Fatty Acids, Nonesterified / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008744:Methylamines / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D011422:Propionates / Q000378:metabolism; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D017962:alpha-Linolenic Acid / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C519853:FFAR4 protein, human; D005230:Fatty Acids, Nonesterified; C515630:GW9508; D008024:Ligands; D008744:Methylamines; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D000071557:beta-Arrestins; D017962:alpha-Linolenic Acid
keywords: 7-Helix Receptor; Bioluminescence Resonance Energy Transfer (BRET); Diabetes; Fatty Acid; G Protein-coupled Receptor (GPCR); Homology Modeling