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

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site. / Shehata, Mohamed A.; Jensen, Anne Cathrine Nøhr; Jespers, Willem; Floryan, Leonard; Isberg, Vignir; Andersen, Kirsten Bayer; Åqvist, Johan; Gutiérrez-de-Terán, Hugo; Bräuner-Osborne, Hans; Gloriam, David E.

In: Scientific Reports, Vol. 7, 1128, 25.04.2017.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Shehata, MA, Jensen, ACN, Jespers, W, Floryan, L, Isberg, V, Andersen, KB, Åqvist, J, Gutiérrez-de-Terán, H, Bräuner-Osborne, H & Gloriam, DE 2017, 'The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site', Scientific Reports, vol. 7, 1128. https://doi.org/10.1038/s41598-017-01049-z

APA

Shehata, M. A., Jensen, A. C. N., Jespers, W., Floryan, L., Isberg, V., Andersen, K. B., ... Gloriam, D. E. (2017). The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site. Scientific Reports, 7, [1128]. https://doi.org/10.1038/s41598-017-01049-z

Vancouver

Shehata MA, Jensen ACN, Jespers W, Floryan L, Isberg V, Andersen KB et al. The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site. Scientific Reports. 2017 Apr 25;7. 1128. https://doi.org/10.1038/s41598-017-01049-z

Author

Shehata, Mohamed A. ; Jensen, Anne Cathrine Nøhr ; Jespers, Willem ; Floryan, Leonard ; Isberg, Vignir ; Andersen, Kirsten Bayer ; Åqvist, Johan ; Gutiérrez-de-Terán, Hugo ; Bräuner-Osborne, Hans ; Gloriam, David E. / The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site. In: Scientific Reports. 2017 ; Vol. 7.

Bibtex

@article{3451489443394021bc1fdab303032d8a,
title = "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 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.",
author = "Shehata, {Mohamed A.} and Jensen, {Anne Cathrine N{\o}hr} and Willem Jespers and Leonard Floryan and Vignir Isberg and Andersen, {Kirsten Bayer} and Johan {\AA}qvist and Hugo Guti{\'e}rrez-de-Ter{\'a}n and Hans Br{\"a}uner-Osborne and Gloriam, {David E.}",
year = "2017",
month = "4",
day = "25",
doi = "10.1038/s41598-017-01049-z",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site

AU - Shehata, Mohamed A.

AU - Jensen, Anne Cathrine Nøhr

AU - Jespers, Willem

AU - Floryan, Leonard

AU - Isberg, Vignir

AU - Andersen, Kirsten Bayer

AU - Åqvist, Johan

AU - Gutiérrez-de-Terán, Hugo

AU - Bräuner-Osborne, Hans

AU - Gloriam, David E.

PY - 2017/4/25

Y1 - 2017/4/25

N2 - 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.

AB - 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.

UR - https://www.nature.com/articles/s41598-017-01049-z

U2 - 10.1038/s41598-017-01049-z

DO - 10.1038/s41598-017-01049-z

M3 - Journal article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 1128

ER -

ID: 176868033