The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site
Abstract GPR139 is an orphan G protein-coupled receptor expressed in the brain, in particular in the habenula, hypothalamus and striatum. It has therefore been suggested that GPR139 is a possible target for metabolic disorders and Parkinson’s disease. Several surrogate agonist series have been publi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-01049-z |
| _version_ | 1818991398765985792 |
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| author | Anne Cathrine Nøhr Willem Jespers Mohamed A. Shehata Leonard Floryan Vignir Isberg Kirsten Bayer Andersen Johan Åqvist Hugo Gutiérrez-de-Terán Hans Bräuner-Osborne David E. Gloriam |
| author_facet | Anne Cathrine Nøhr Willem Jespers Mohamed A. Shehata Leonard Floryan Vignir Isberg Kirsten Bayer Andersen Johan Åqvist Hugo Gutiérrez-de-Terán Hans Bräuner-Osborne David E. Gloriam |
| author_sort | Anne Cathrine Nøhr |
| collection | DOAJ |
| description | Abstract GPR139 is an orphan G protein-coupled receptor expressed in the brain, in particular in the habenula, hypothalamus and striatum. It has therefore been suggested that GPR139 is a possible target for metabolic disorders and Parkinson’s disease. Several surrogate agonist series have been published for GPR139. Two series published by Shi et al. and Dvorak et al. included agonists 1a and 7c respectively, with potencies in the ten-nanomolar range. Furthermore, Isberg et al. and Liu et al. have previously shown that tryptophan (Trp) and phenylalanine (Phe) can activate GPR139 in the hundred-micromolar range. In this study, we produced a mutagenesis-guided model of the GPR139 binding site to form a foundation for future structure-based ligand optimization. Receptor mutants studied in a Ca2+ assay demonstrated that residues F1093×33, H1875×43, W2416×48 and N2717×38, but not E1083×32, are highly important for the activation of GPR139 as predicted by the receptor model. The initial ligand-receptor complex was optimized through free energy perturbation simulations, generating a refined GPR139 model in agreement with experimental data. In summary, the GPR139 reference surrogate agonists 1a and 7c, and the endogenous amino acids l-Trp and l-Phe share a common binding site, as demonstrated by mutagenesis, ligand docking and free energy calculations. |
| first_indexed | 2024-12-20T20:09:38Z |
| format | Article |
| id | doaj.art-17e7b959f6554066a99116d9312ac208 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-20T20:09:38Z |
| publishDate | 2017-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-17e7b959f6554066a99116d9312ac2082022-12-21T19:27:51ZengNature PortfolioScientific Reports2045-23222017-04-01711910.1038/s41598-017-01049-zThe GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding siteAnne Cathrine Nøhr0Willem Jespers1Mohamed A. Shehata2Leonard Floryan3Vignir Isberg4Kirsten Bayer Andersen5Johan Åqvist6Hugo Gutiérrez-de-Terán7Hans Bräuner-Osborne8David E. Gloriam9Department of Drug Design and Pharmacology, University of CopenhagenDepartment of Cell and Molecular Biology, Uppsala University, Biomedical CenterDepartment of Drug Design and Pharmacology, University of CopenhagenDepartment of Chemistry and Applied BiosciencesDepartment of Drug Design and Pharmacology, University of CopenhagenDepartment of Drug Design and Pharmacology, University of CopenhagenDepartment of Cell and Molecular Biology, Uppsala University, Biomedical CenterDepartment of Cell and Molecular Biology, Uppsala University, Biomedical CenterDepartment of Drug Design and Pharmacology, University of CopenhagenDepartment of Drug Design and Pharmacology, University of CopenhagenAbstract GPR139 is an orphan G protein-coupled receptor expressed in the brain, in particular in the habenula, hypothalamus and striatum. It has therefore been suggested that GPR139 is a possible target for metabolic disorders and Parkinson’s disease. Several surrogate agonist series have been published for GPR139. Two series published by Shi et al. and Dvorak et al. included agonists 1a and 7c respectively, with potencies in the ten-nanomolar range. Furthermore, Isberg et al. and Liu et al. have previously shown that tryptophan (Trp) and phenylalanine (Phe) can activate GPR139 in the hundred-micromolar range. In this study, we produced a mutagenesis-guided model of the GPR139 binding site to form a foundation for future structure-based ligand optimization. Receptor mutants studied in a Ca2+ assay demonstrated that residues F1093×33, H1875×43, W2416×48 and N2717×38, but not E1083×32, are highly important for the activation of GPR139 as predicted by the receptor model. The initial ligand-receptor complex was optimized through free energy perturbation simulations, generating a refined GPR139 model in agreement with experimental data. In summary, the GPR139 reference surrogate agonists 1a and 7c, and the endogenous amino acids l-Trp and l-Phe share a common binding site, as demonstrated by mutagenesis, ligand docking and free energy calculations.https://doi.org/10.1038/s41598-017-01049-z |
| spellingShingle | Anne Cathrine Nøhr Willem Jespers Mohamed A. Shehata Leonard Floryan Vignir Isberg Kirsten Bayer Andersen Johan Åqvist Hugo Gutiérrez-de-Terán Hans Bräuner-Osborne David E. Gloriam The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site Scientific Reports |
| title | The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site |
| title_full | The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site |
| title_fullStr | The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site |
| title_full_unstemmed | The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site |
| title_short | The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site |
| title_sort | gpr139 reference agonists 1a and 7c and tryptophan and phenylalanine share a common binding site |
| url | https://doi.org/10.1038/s41598-017-01049-z |
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