Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case

Abstract Bitter taste is one of the basic taste modalities, warning against consuming potential poisons. Bitter compounds activate members of the bitter taste receptor (Tas2r) subfamily of G protein-coupled receptors (GPCRs). The number of functional Tas2rs is species-dependent. Chickens represent a...

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Autores principales:	Antonella Di Pizio, Louisa-Marie Kruetzfeldt, Shira Cheled-Shoval, Wolfgang Meyerhof, Maik Behrens, Masha Y. Niv
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f2c51f37776d4a93b2eea86820a84d7a
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spelling	oai:doaj.org-article:f2c51f37776d4a93b2eea86820a84d7a2021-12-02T12:30:26ZLigand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case10.1038/s41598-017-08344-92045-2322https://doaj.org/article/f2c51f37776d4a93b2eea86820a84d7a2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08344-9https://doaj.org/toc/2045-2322Abstract Bitter taste is one of the basic taste modalities, warning against consuming potential poisons. Bitter compounds activate members of the bitter taste receptor (Tas2r) subfamily of G protein-coupled receptors (GPCRs). The number of functional Tas2rs is species-dependent. Chickens represent an intriguing minimalistic model, because they detect the bitter taste of structurally different molecules with merely three bitter taste receptor subtypes. We investigated the binding modes of several known agonists of a representative chicken bitter taste receptor, ggTas2r1. Because of low sequence similarity between ggTas2r1 and crystallized GPCRs (~10% identity, ~30% similarity at most), the combination of computational approaches with site-directed mutagenesis was used to characterize the agonist-bound conformation of ggTas2r1 binding site between TMs 3, 5, 6 and 7. We found that the ligand interactions with N93 in TM3 and/or N247 in TM5, combined with hydrophobic contacts, are typically involved in agonist recognition. Next, the ggTas2r1 structural model was successfully used to identify three quinine analogues (epiquinidine, ethylhydrocupreine, quinidine) as new ggTas2r1 agonists. The integrated approach validated here may be applicable to additional cases where the sequence identity of the GPCR of interest and the existing experimental structures is low.Antonella Di PizioLouisa-Marie KruetzfeldtShira Cheled-ShovalWolfgang MeyerhofMaik BehrensMasha Y. NivNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Antonella Di Pizio Louisa-Marie Kruetzfeldt Shira Cheled-Shoval Wolfgang Meyerhof Maik Behrens Masha Y. Niv Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case
description	Abstract Bitter taste is one of the basic taste modalities, warning against consuming potential poisons. Bitter compounds activate members of the bitter taste receptor (Tas2r) subfamily of G protein-coupled receptors (GPCRs). The number of functional Tas2rs is species-dependent. Chickens represent an intriguing minimalistic model, because they detect the bitter taste of structurally different molecules with merely three bitter taste receptor subtypes. We investigated the binding modes of several known agonists of a representative chicken bitter taste receptor, ggTas2r1. Because of low sequence similarity between ggTas2r1 and crystallized GPCRs (~10% identity, ~30% similarity at most), the combination of computational approaches with site-directed mutagenesis was used to characterize the agonist-bound conformation of ggTas2r1 binding site between TMs 3, 5, 6 and 7. We found that the ligand interactions with N93 in TM3 and/or N247 in TM5, combined with hydrophobic contacts, are typically involved in agonist recognition. Next, the ggTas2r1 structural model was successfully used to identify three quinine analogues (epiquinidine, ethylhydrocupreine, quinidine) as new ggTas2r1 agonists. The integrated approach validated here may be applicable to additional cases where the sequence identity of the GPCR of interest and the existing experimental structures is low.
format	article
author	Antonella Di Pizio Louisa-Marie Kruetzfeldt Shira Cheled-Shoval Wolfgang Meyerhof Maik Behrens Masha Y. Niv
author_facet	Antonella Di Pizio Louisa-Marie Kruetzfeldt Shira Cheled-Shoval Wolfgang Meyerhof Maik Behrens Masha Y. Niv
author_sort	Antonella Di Pizio
title	Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case
title_short	Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case
title_full	Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case
title_fullStr	Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case
title_full_unstemmed	Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case
title_sort	ligand binding modes from low resolution gpcr models and mutagenesis: chicken bitter taste receptor as a test-case
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f2c51f37776d4a93b2eea86820a84d7a
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Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case

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