Abstract
The human T1R2-T1R3 sweet taste receptor (STR) plays an important role in recognizing various low-molecular-weight sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception. Xylitol and sorbitol, which are naturally occurring sugar alcohols (polyols) found in many fruits and vegetables, exhibit the potential caries-reducing effect and are widely used for diabetic patients as low-calorie sweeteners. In the present study, computational tools were applied to investigate the structural details of binary complexes formed between these two polyols and the T1R2-T1R3 heterodimeric STR. Principal component analysis revealed that the Venus flytrap domain (VFD) of T1R2 monomer was adapted by the induced-fit mechanism to accommodate the focused polyols, in which residues 233–268 moved significantly closer to stabilize ligands. This finding likely suggested that these structural transformations might be the important mechanisms underlying polyols-STR recognitions. The calculated free energies also supported the VFD of T1R2 monomer as the preferential binding site for such polyols, rather than T1R3 region, in accord with the lower number of accessible water molecules in the T1R2 pocket. The E302 amino acid residue in T1R2 was found to be the important recognition residue for polyols binding through a strongly formed hydrogen bond. Additionally, the binding affinity of xylitol toward the T1R2 monomer was significantly higher than that of sorbitol, making it a sweeter tasting molecule.
Highlights
The human taste 1 receptor (T1R) member 2 (T1R2)-T1R member 3 (T1R3) sweet taste receptor (STR) plays an important role in recognizing various low-molecular-weight sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception
The results revealed that each sugar alcohol binding dramatically converted the direction of motions to point toward the ligands in both T1R2 and T1R3 monomers, in a manner different from that of the apo-protein
As (i) xylitol and sorbitol preferentially bind to Venus flytrap domain (VFD) of STR rather than to transmembrane domain (TMD) and cysteine-rich domain (CRD) (Table S1) and (ii) the structural adaptation of VFD induced by sugar alcohols has not yet been fully revealed, we, focused on only VFD for investigating the atomistic binding mechanisms upon polyols recognition
Summary
The human T1R2-T1R3 sweet taste receptor (STR) plays an important role in recognizing various low-molecular-weight sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein that in turn leads to the sweet taste perception. Xylitol and sorbitol, which are naturally occurring sugar alcohols (polyols) found in many fruits and vegetables, exhibit the potential caries-reducing effect and are widely used for diabetic patients as low-calorie sweeteners. Xylitol and sorbitol (Fig. 1A,B) are representative sugar alcohols ( known as polyols) that are naturally found in many fruits and vegetables and can serve as an alternative less controversial sweetener with a caries-reducing effect[9] They are widely utilized in the diet of diabetic patients as low-calorie www.nature.com/scientificreports/. The T1R2-T1R3 STR expressed on the surface of the tongue[14] can be activated by a broad range of sweet-tasting molecules, including sugars (monosaccharides and disaccharides), artificial sweeteners (saccharin and cyclamates), amino acids (tryptophan, serine, and phenylalanine)[12], small sweet-tasting proteins (thaumatin, monellin, brazzein, and neoculin)[15], and sugar alcohols (sorbitol and xylitol)[16,17]. The structural details as well as the mechanisms underlying the activation of STR by small molecule sweeteners and proteins have been investigated[15,22,23], the structural dynamics, intermolecular interactions at the atomic level, and the preferential binding site of the two polyols, xylitol and sorbitol, toward STR remain largely unexplored
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