Structure-Function Analyses of Human Bitter Taste Receptors-Where Do We Stand?

Abstract

The finding that bitter taste receptors are expressed in numerous tissues outside the oral cavity and fulfill important roles in metabolic regulation, innate immunity and respiratory control, have made these receptors important targets for drug discovery. Efficient drug discovery depends heavily on detailed knowledge on structure-function-relationships of the target receptors. Unfortunately, experimental structures of bitter taste receptors are still lacking, and hence, the field relies mostly on structures obtained by molecular modeling combined with functional experiments and point mutageneses. The present article summarizes the current knowledge on the structure-function relationships of human bitter taste receptors. Although these receptors are difficult to express in heterologous systems and their homology with other G protein-coupled receptors is very low, detailed information are available at least for some of these receptors.

Keywords: GPCR; TAS2R; bitter taste receptor; molecular modeling.

Figure 1

Idealized dose-response relationships of functional receptor assays. The unmodified receptor (circles, green) responses (x-axis, set to 100%) are plotted as a function of the agonist concentration (x-axis, logarithmically scaled). The fictitious receptor mutant A (squares, red) shows a right shift of the curve; however, it reaches the maximal response magnitude of the unmodified receptor. Since only the agonist concentration needs to be raised to achieve an activation similar to the unmodified receptor, the interaction of the agonist with the receptor’s binding pocket seems to be weakened by this mutation. The fictitious receptor mutant B (triangles, cyan) exhibits only maximal amplitudes of 50% of the unmodified receptor; however, the EC₅₀-concentration (concentration at which half-maximal receptor activation is reached) is identical. In this case, one can assume that the residue mutated in mutant B is important for the activation by the agonist but not in the binding, since identical agonist concentrations result in similar proportional receptor activities. Finally, fictitious receptor mutant C (diamonds, blue) shows a drop in maximal signal amplitude as well as a shift in the EC₅₀-concentration, making interpretations of the underlying reason(s) difficult to impossible. In fact, this type of behavior is sometimes observed when in vitro mutagenesis is combined with functional assays.

Figure 2

Flow chart illustrating the typical steps involved in structure-function studies. The taste 2 receptor (TAS2R) ribbon model was taken from bitterDB [88,89]. The graphs do not rely on experimental data; they were drawn for illustration purposes only.