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.