Differences and Similarities between Bitter Taste Receptors and Class A GPCRs

Bitter taste is one of the basic taste modalities and is typically considered as anti-ingestive signal against poison consumption. Recently bitter taste receptors (T2Rs) were shown to be expressed extraorally, emerging as potential novel drug targets. T2Rs have numerous and diverse agonists, a better understanding of molecular recognition of bitter compounds may potentially help discover novel drugs.

T2Rs represent a separate branch usually associated with Class A GPCRs. T2Rs similarity to Class A GPCRs is very low (13-29% for the TM domains), and some of the typical Class A sequence motifs, such as the TM3 D[E]RY and the ECL2-TM3 disulfide bridge are missing. This suggests an alternative mode of regulating conformational states, with possibly a less stabilized inactive state. Moreover, most of the known bitter ligands are agonists, with only a few antagonists documented thus far. The agonists-to-antagonists ratios of GPCRs are variable but much lower than for T2Rs.

The ligand binding pocket of T2Rs coincides with the canonical binding site of Class A GPCRs, and several positions were shown to be involved in agonist binding in both GPCRs and T2Rs. We previously found that GPCR promiscuity towards antagonists correlates with binding site exposure and hydrophobicity. Similar features were also found to underlie the promiscuity of T2Rs towards their agonists. Interestingly, the analysis of existing Xray complexes suggests differential involvement of Class A GPCR regions in binding of agonists vs antagonists.

Our findings show that while promiscuity towards ligands is a general GPCRs feature, T2Rs are unique in terms of high agonist/antagonist ratio and overall low affinity towards ligands. These characteristics may be related to the T2R sequence and structural motifs, but require further investigation.