Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists

Rafik Karaman, Stefanie Nowak, Antonella Di Pizio, Hothaifa Kitaneh, Alaa Abu-Jaish, Wolfgang Meyerhof, Masha Y. Niv, Maik Behrens*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Sensing potentially harmful bitter substances in the oral cavity is achieved by a group of ˜25 receptors, named TAS2Rs, which are expressed in specialized sensory cells and recognize individual but overlapping sets of bitter compounds. The receptors differ in their tuning breadths ranging from narrowly to broadly tuned receptors. One of the most broadly tuned human bitter taste receptors is the TAS2R14 recognizing an enormous variety of chemically diverse synthetic and natural bitter compounds, including numerous medicinal drugs. This suggests that this receptor possesses a large readily accessible ligand binding pocket. To allow probing the accessibility and size of the ligand binding pocket, we chemically modified cognate agonists and tested receptor responses in functional assays. The addition of large functional groups to agonists was usually possible without abolishing agonistic activity. The newly synthesized agonist derivatives were modeled in the binding site of the receptor, providing comparison to the mother substances and rationalization of the in vitro activities of this series of compounds.

Original languageAmerican English
Pages (from-to)66-75
Number of pages10
JournalChemical Biology and Drug Design
DOIs
StatePublished - 1 Jul 2016

Bibliographical note

Publisher Copyright:
© 2016 John Wiley & Sons A/S

Keywords

  • TAS2R binding pocket
  • bitter taste receptor
  • chemical ligand design
  • functional calcium imaging
  • in silico homology modeling

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