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Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor.

ABSTRACT: Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radioligand binding interaction studies revealed that the full agonists do not bind to the same site as the partial agonists but exhibit positive heterotropic cooperativity. Analysis of functional data reveals positive functional cooperativity between the full agonists and partial agonists in various functional assays (in vitro and ex vivo) and also in vivo. Furthermore, the endogenous fatty acid docosahexaenoic acid (DHA) shows negative or neutral cooperativity with members of both series of agonists in binding assays but displays positive cooperativity in functional assays. Another synthetic agonist is allosteric with members of both agonist series, but apparently competitive with DHA. Therefore, there appear to be three allosterically linked binding sites on FFA1 with agonists specific for each of these sites. Activation of free fatty acid 1 receptor (FFAR1) by each of these agonists is differentially affected by mutations of two arginine residues, previously found to be important for FFAR1 binding and activation. These ligands with their high potencies and strong positive functional cooperativity with endogenous fatty acids, demonstrated in vitro and in vivo, have the potential to deliver therapeutic benefits.

SUBMITTER: Lin DC

PROVIDER: S-EPMC3477236 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor.

Lin Daniel C-H DC Guo Qi Q Luo Jian J Zhang Jane J Nguyen Kathy K Chen Michael M Tran Thanh T Dransfield Paul J PJ Brown Sean P SP Houze Jonathan J Vimolratana Marc M Jiao Xian Yun XY Wang Yingcai Y Birdsall Nigel J M NJ Swaminath Gayathri G

Molecular pharmacology 20120802 5

Activation of FFA1 (GPR40), a member of G protein-coupling receptor family A, is mediated by medium- and long-chain fatty acids and leads to amplification of glucose-stimulated insulin secretion, suggesting a potential role for free fatty acid 1 (FFA1) as a target for type 2 diabetes. It was assumed previously that there is a single binding site for fatty acids and synthetic FFA1 agonists. However, using members of two chemical series of partial and full agonists that have been identified, radio ...[more]

PMID: 22859723

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Project description:BackgroundFragment-based ligand design is used for the development of novel ligands that target macromolecules, most notably proteins. Central to its success is the identification of fragment binding sites that are spatially adjacent such that fragments occupying those sites may be linked to create drug-like ligands. Current experimental and computational approaches that address this problem typically identify only a limited number of sites as well as use a limited number of fragment types.MethodsThe site-identification by ligand competitive saturation (SILCS) approach is extended to the identification of fragment bindings sites, with the method termed SILCS-Hotspots. The approach involves precomputation of the SILCS FragMaps following which the identification of Hotspots, performed by identifying of all possible fragment binding sites on the full 3D structure of the protein followed by spatial clustering.ResultsThe SILCS-Hotspots approach identifies a large number of sites on the target protein, including many sites not accessible in experimental structures due to low binding affinities and binding sites on the protein interior. The identified sites are shown to recapitulate the location of known drug-like molecules in both allosteric and orthosteric binding sites on seven proteins including the androgen receptor, the CDK2 and Erk5 kinases, PTP1B phosphatase and three GPCRs; the β2-adrenergic, GPR40 fatty-acid binding and M2-muscarinic receptors. Analysis indicates the importance of considering all possible fragment binding sites, and not just those accessible to experimental methods, when identifying novel binding sites and performing ligand design versus just considering the most favorable sites. The approach is shown to identify a larger number of known binding sites of drug-like molecules versus the commonly used FTMap and Fpocket methods.General significanceThe present results indicate the potential utility of the SILCS-Hotspots approach for fragment-based rational design of ligands, including allosteric modulators.

Dataset Information

Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor.

Publications

Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor.

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