The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site

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Date
2017-04-25Type
- Journal Article
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Cited 17 times in
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Cited 18 times in
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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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000191267Publication status
publishedExternal links
Journal / series
Scientific ReportsVolume
Pages / Article No.
Publisher
Nature Publishing GroupSubject
Computational models; Receptor pharmacologyMore
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Citations
Cited 17 times in
Web of Science
Cited 18 times in
Scopus
ETH Bibliography
yes
Altmetrics