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

Stefanie Nowak, Antonella Di Pizio, Anat Levit, Masha Y. Niv, Wolfgang Meyerhof, Maik Behrens

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: Since numerous modifications of the TAS2R14 binding pocket resulted in improved responses to individual agonists, we conclude that this bitter taste receptor might represent a suitable template for the engineering of the agonist profile of a chemoreceptive receptor. General significance: The detailed structure-function analysis of the highly promiscuous and widely expressed TAS2R14 suggests that this receptor must be considered as potentially frequent target for known and novel drugs including undesired off-effects.

Original languageEnglish
Pages (from-to)2162-2173
Number of pages12
JournalBiochimica et Biophysica Acta - General Subjects
Volume1862
Issue number10
DOIs
StatePublished - Oct 2018
Externally publishedYes

Keywords

  • Bitter taste receptor
  • Calcium imaging
  • G protein-coupled receptor (GPCR)
  • In vitro mutagenesis
  • Molecular modeling
  • Structure-function relationship

Fingerprint

Dive into the research topics of 'Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14'. Together they form a unique fingerprint.

Cite this