Sweet chirality: the taste of l- and d-glucose stereoisomers

Chirality plays a key role in biomolecular recognition. Typically, a change in chirality will dramatically affect ligand–receptor binding. However, both d-glucose and its enantiomer l-glucose elicit sweet taste in humans. We show that l- and d-glucose are perceived as similarly sweet by humans, and that in cell-based functional assays, both enantiomers activate the human sweet taste receptor TAS1R2/TAS1R3. We hypothesize that both l- and d-glucose occupy the orthosteric binding site in the VFT domain of TAS1R2. Using induced-fit docking to a homology model of this domain, we identify two subpockets in this binding site. The model suggests that glucose molecules can bind in either of these subpockets, which overlap with the predicted positions of monosaccharide units of sucrose. One subpocket is close to the hinge between the two lobes, and overlaps with aspartame and neotame site, the second subpocket overlaps with that described for sweetness enhancers. These findings suggest a framework for rational design of sweeteners combinations.