Atomistic Mechanisms Underlying the Activation of G Protein-Coupled Sweet Receptor Heterodimer Mediated by Sugar Alcohol Recognition

Abstract

The human sweet taste receptor (T1R2-T1R3) plays an important role in recognizing various low-molecular-weight sweet-tasting sugars and proteins, resulting in the release of intracellular heterotrimeric G protein, which leads to a sweet taste perception. Xylitol and sorbitol, which are sugar alcohols naturally 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, the computational tools are applied to investigate the structural details of binary complexes formed between sugar alcohols and T1R2-T1R3 heterodimeric receptor. Principle component analysis reveals that the ligand-binding site in T1R2 domain is adapted by the induced-fit mechanism to accommodate the focused sugar alcohols, in which the residues 233-268 are significantly located closer to stabilize ligand. The finding likely suggests that these structural transformations might be the important mechanisms underlying ligand-protein recognitions. The calculated free energies also support the aminoterminal domain of T1R2 monomer as the preferential binding site for such sugar alcohols rather than T1R3 domain, in a correspondence with relatively less water molecules accessible into the T1R2 pocket. The T1R2 E302 residue is found to be the important recognized residue for sugar alcohol binding through a strongly firmed hydrogen bond and electrostatic attraction. Additionally, the binding affinity of xylitol toward T1R2 domain is significantly higher than that of sorbitol, making it a sweeter taste molecule.