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The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site
Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Vladimir Prelog Weg 1-5-10, CH-8093 Zurich, Switzerland..
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 1128Article in journal (Refereed) Published
Abstract [en]

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 F109(3x33), H187(5x43), W241(6x48) and N271(7x38), but not E108(3x32), 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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 7, 1128
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Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-322726DOI: 10.1038/s41598-017-01049-zISI: 000400104200017PubMedID: 28442765OAI: oai:DiVA.org:uu-322726DiVA: diva2:1099116
Funder
Swedish Research Council
Available from: 2017-05-29 Created: 2017-05-29 Last updated: 2017-05-29Bibliographically approved

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