title: Application of GPCR Structures for Modelling of Free Fatty Acid Receptors.
abstract: Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge-pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small-molecule modulators at the FFA receptors.
authors.affiliation: Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, BT9 7BL, Northern Ireland, UK. i.tikhonova@qub.ac.uk.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011956:Receptors, Cell Surface / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*
chemical_list: D005230:Fatty Acids, Nonesterified; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C473103:FFAR2 protein, human; C473034:FFAR1 protein, human; C106262:FFAR3 protein, human; C519853:FFAR4 protein, human; C431700:GPR84 protein, human
keywords: Allosteric site; FFA1; FFA2; FFA3; FFA4; Free fatty acid receptors; G protein-coupled receptors; GPR84; Molecular modelling; Mutagenesis; Orthosteric site; SAR