Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14

Biochimica Et Biophysica Acta. General Subjects
Stefanie NowakMaik Behrens

Abstract

In humans, bitterness perception is mediated by ~25 bitter taste receptors present in the oral cavity. Among these receptors three, TAS2R10, TAS2R14 and TAS2R46, exhibit extraordinary wide agonist profiles and hence contribute disproportionally high to the perception of bitterness. Perhaps the most broadly tuned receptor is the TAS2R14, which may represent, because of its prominent expression in extraoral tissues, a receptor of particular importance for the physiological actions of bitter compounds beyond taste. To investigate how the architecture and composition of the TAS2R14 binding pocket enables specific interactions with a complex array of chemically diverse bitter agonists, we carried out homology modeling and ligand docking experiments, subjected the receptor to point-mutagenesis of binding site residues and performed functional calcium mobilization assays. In total, 40 point-mutated receptor constructs were generated to investigate the contribution of 19 positions presumably located in the receptor's binding pocket to activation by 7 different TAS2R14 agonists. All investigated positions exhibited moderate to pronounced agonist selectivity. Since numerous modifications of the TAS2R14 binding pocket resulted in improved...Continue Reading

Citations

Oct 26, 2018·Nucleic Acids Research·Ayana Dagan-WienerMasha Y Niv
Feb 28, 2020·Experimental and Therapeutic Medicine·Hongling ZhuXiangqi Li
Mar 23, 2019·International Journal of Molecular Sciences·Antonella Di PizioDietmar Krautwurst
May 28, 2020·Frontiers in Physiology·Conor J BloxhamWalter G Thomas
Oct 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Maik Behrens, Florian Ziegler
Jun 27, 2019·Cellular and Molecular Life Sciences : CMLS·Antonella Di PizioMasha Y Niv
Jan 5, 2021·Frontiers in Pharmacology·Raise Ahmad, Julie E Dalziel
Dec 24, 2020·Genome Biology and Evolution·Maik BehrensSigrun I Korsching
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Oct 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Antonella Di Pizio, Alessandro Nicoli
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Dec 22, 2020·ACS Pharmacology & Translational Science·Donghwa KimStephen B Liggett
May 22, 2020·Journal of Agricultural and Food Chemistry·Tatjana LangMaik Behrens

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