Abstract
The 25 human bitter taste receptors (hT2Rs) recognize thousands of structurally and chemically diverse bitter substances. The binding modes of human bitter taste receptors hT2R10 and hT2R46, which are responsible for strychnine recognition, were previously established using site-directed mutagenesis, functional assays, and molecular modeling. Here we construct a phylogenetic tree and reconstruct ancestral sequences of the T2R10 and T2R46 clades. We next analyze the binding sites in view of experimental data to predict their ability to recognize strychnine. This analysis suggests that the common ancestor of hT2R10 and hT2R46 is unlikely to bind strychnine in the same mode as either of its two descendants. Estimation of relative divergence times shows that hT2R10 evolved earlier than hT2R46. Strychnine recognition was likely acquired first by the earliest common ancestor of the T2R10 clade before the separation of primates from other mammals, and was highly conserved within the clade. It was probably independently acquired by the common ancestor of T2R43-47 before the homo-ape speciation, lost in most T2Rs within this clade, but enhanced in the hT2R46 after humans diverged from the rest of primates. Our findings suggest hypothetical strychnine T2R receptors in several species, and serve as an experimental guide for further study. Improved understanding of how bitter taste receptors acquire the ability to be activated by particular ligands is valuable for the development of sensors for bitterness and for potential toxicity.
Highlights
Bitterness perception is considered a key defense mechanism against the ingestion of potentially toxic substances (Chandrashekar et al, 2000)
Key ligand-binding positions that were elucidated in previous studies (Reichling et al, 2008; Brockhoff et al, 2010; Born et al, 2013; Sandal et al, 2015) were analyzed, and, using known mutagenesis data, the potential effects on strychnine interactions due to evolutionary variation at these positions were predicted. hT2R46 and hT2R10 models in complex with strychnine were used to discuss the roles of key positions in the 3D structural context
The bitter taste receptors hT2R10 and hT2R46 are activated by strychnine
Summary
Bitterness perception is considered a key defense mechanism against the ingestion of potentially toxic substances (Chandrashekar et al, 2000). The recognition of bitter molecules is mediated by a set of chemosensory receptors denoted as taste receptors type 2 (T2Rs or TAS2Rs), which belong to the superfamily of G protein-coupled receptors (GPCRs). The 25 hT2Rs recognize bitter compounds of wide chemical diversity (Wiener et al, 2012; Di Pizio and Niv, 2015; Behrens and Meyerhof, 2017). Many T2Rs, such as human T2R14, T2R10, and T2R46 are activated by many chemically diverse bitter compounds, while other subtypes are more selective (Di Pizio and Niv, 2015; Behrens and Meyerhof, 2017)
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