Dual binding mode of “bitter sugars” to their human bitter taste receptor target

Abstract

The 25 human bitter taste receptors (hTAS2Rs) are responsible for detecting bitter molecules present in food, and they also play several physiological and pathological roles in extraoral compartments. Therefore, understanding their ligand specificity is important both for food research and for pharmacological applications. Here we provide a molecular insight into the exquisite molecular recognition of bitter β-glycopyranosides by one of the members of this receptor subclass, hTAS2R16. Most of its agonists have in common the presence of a β-glycopyranose unit along with an extremely structurally diverse aglycon moiety. This poses the question of how hTAS2R16 can recognize such a large number of “bitter sugars”. By means of hybrid molecular mechanics/coarse grained molecular dynamics simulations, here we show that the three hTAS2R16 agonists salicin, arbutin and phenyl-β-D-glucopyranoside interact with the receptor through a previously unrecognized dual binding mode. Such mechanism may offer a seamless way to fit different aglycons inside the binding cavity, while maintaining the sugar bound, similar to the strategy used by several carbohydrate-binding lectins. Our prediction is validated a posteriori by comparison with mutagenesis data and also rationalizes a wealth of structure-activity relationship data. Therefore, our findings not only provide a deeper molecular characterization of the binding determinants for the three ligands studied here, but also give insights applicable to other hTAS2R16 agonists. Together with our results for other hTAS2Rs, this study paves the way to improve our overall understanding of the structural determinants of ligand specificity in bitter taste receptors.

In Silico Molecular Study of Tryptophan Bitterness

“…Tryptophan was surrounded by numerous hydrophobic/aromatic residues (Phe88 3.32 , Met89 3.33 , Tyr242 6.51 ) and was predicted to interact with Tyr242 6.51 and Thr246 6.55 through π–π and H-bond interactions, respectively. Both BW positions 6.51 [ 23 , 24 , 30 , 31 , 32 , 33 ] and 6.55 [ 30 , 31 , 34 ] were previously indicated as agonist-interacting positions in other bitter taste receptors. Moreover, these interactions are indeed predicted to be maintained for di-tryptophan and tri-tryptophan ( Figure 2 ), suggesting that the sub-pocket around Phe88 3.32 and Tyr242 6.51 is the best epitope for the recognition of tryptophan by TAS2R4 (TAS2R4 epitope 1, Figures S2A and S3A ).…”

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

“…However, it turned out that several structure-function studies showed discrepancies with regard to the binding modes of agonists and, consequently, the receptor positions involved in agonist binding [ 102 , 103 , 104 , 105 ]. The most recent report by Fierro et al concluded that, depending on the agonist, residues in TM II, III, V, VI and VII are responsible for ligand binding [ 106 ]. For the human TAS2R38, TM III, V and VI are proposed to be involved in the binding of its agonists phenylthiocarbamide (PTC) and 6-n-propyl-thiouracil (PROP) [ 107 , 108 , 109 ].…”

The future of bronchodilation: looking for new classes of bronchodilators

“…Bitter-taste or taste type 2 receptors (TAS2Rs) are a group of 25 proteins belonging to the GPCR superfamily that have been identified in the taste buds of the tongue and also in extraoral tissues, including respiratory epithelia and smooth muscle [39]. They are classified as class A GPCRs for their architecture and binding site location [40].…”