title: Bidirectional, iterative approach to the structural delineation of the functional "chemoprint" in GPR40 for agonist recognition.
abstract: GPR40, free fatty acid receptor 1 (FFAR1), is a member of the GPCR superfamily and a possible target for the treatment of type 2 diabetes. In this work, we conducted a bidirectional iterative investigation, including computational modeling and site-directed mutagenesis, aimed at delineating amino acid residues forming the functional "chemoprint" of GPR40 for agonist recognition. The computational and experimental studies revolved around the recognition of the potent synthetic agonist GW9508. Our experimentally supported model suggested that H137(4.56), R183(5.39), N244(6.55), and R258(7.35) are directly involved in interactions with the ligand. We have proposed a polarized NH-pi interaction between H137(4.56) and GW9508 as one of the contributing forces leading to the high potency of GW9508. The modeling approach presented in this work provides a general strategy for the exploration of receptor-ligand interactions in G-protein coupled receptors beginning prior to acquisition of experimental data.
authors.affiliation: Laboratory of Biological Modeling, Clinical Endocrinology Branch, Chemical Biology Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Tikhonova
authors.forename: Chi Shing
authors.initials: CS
authors.lastname: Sum
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Raaka
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D020539:Sequence Analysis, Protein
chemical_list: C473034:FFAR1 protein, human; C515630:GW9508; D008024:Ligands; D008744:Methylamines; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D002118:Calcium