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Defining the molecular mode of binding for α‐linolenic acid and the synthetic ligand TUG891 at GPR120
Author(s) -
Hudson Brian,
Shimpukade Bharat,
Ulven Trond,
Milligan Graeme
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.655.2
Subject(s) - gpr120 , free fatty acid receptor 1 , ligand (biochemistry) , chemistry , stereochemistry , receptor , biochemistry , g protein coupled receptor , agonist
GPR120 is a receptor for long chain polyunsaturated fatty acids that has received growing interest in recent years for the treatment of type 2 diabetes and obesity. However, its development and validation as a therapeutic target has been hindered by a lack of selective ligands for GPR120 over another long chain fatty acid receptor, FFA1. While the recent description of 3‐(4‐((4‐fluoro‐4’‐methyl‐[1,1’‐biphenyl]‐2‐yl)methoxy)phenyl) propanoic acid (TUG891) as a potent and selective GPR120 agonist improved this situation, the need remains for novel GPR120 ligands. To facilitate ligand development at GPR120 we employed homology models and extensive mutagenesis to define the mode of binding at this receptor for an endogenous ligand, α‐linolenic acid (aLA), and TUG891. These studies confirmed that an ionic interaction between the carboxylate of the ligand with R99 of GPR120 is critical to both aLA and TUG891. Several additional residues, including W104, F115, F211, and W277, were found to define the hydrophobic binding pocket and their mutation reduced function to both aLA and TUG891. Finally, mutation of a group of residues including T119, I280 and I281 predicted to form a narrow binding pocket for the planar biphenyl moiety of TUG891 altered potency of TUG891 but not aLA. Together, our findings define key aspects of ligand interaction for both aLA and TUG891 and will be valuable in future drug development at GPR120.