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Structural basis for GPR40 allosteric agonism and incretin stimulation.

ABSTRACT: Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a G?q-coupled partial agonist, compound 1 is a dual G?q and G?s-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), ?-linolenic acid, can be computationally modeled in this site. Both ?-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.

SUBMITTER: Ho JD

PROVIDER: S-EPMC5917010 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Structural basis for GPR40 allosteric agonism and incretin stimulation.

Ho Joseph D JD Chau Betty B Rodgers Logan L Lu Frances F Wilbur Kelly L KL Otto Keith A KA Chen Yanyun Y Song Min M Riley Jonathan P JP Yang Hsiu-Chiung HC Reynolds Nichole A NA Kahl Steven D SD Lewis Anjana Patel AP Groshong Christopher C Madsen Russell E RE Conners Kris K Lineswala Jayana P JP Gheyi Tarun T Saflor Melbert-Brian Decipulo MD Lee Matthew R MR Benach Jordi J Baker Kenton A KA Montrose-Rafizadeh Chahrzad C Genin Michael J MJ Miller Anne R AR Hamdouchi Chafiq C

Nature communications 20180425 1

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs ...[more]

PMID: 29695780

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Project description:GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic β cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.

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Structural basis for GPR40 allosteric agonism and incretin stimulation.

Publications

Structural basis for GPR40 allosteric agonism and incretin stimulation.

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