Multiple receptors or multiple sites? Modeling the human T1R2-T1R3 sweet taste receptor

T1R2-T1R3, the sweet taste receptor, is activated by a great variety of sweet compounds. In order to understand its ability to bind molecules belonging to diverse chemical classes and a wide range of dimensions, we undertook a systematic homology modelling, using the metabotropic glutamate mGluR1 receptor as template. All possible heterodimers that can be formed by human T1R2 and T1R3 subunits, modelled on the different conformations of mGluR1 protomers yield four different ligand binding sites for low-molecular weight sweeteners. These sites, when probed by docking a set of molecules representative of all classes of sweet compounds, yield free energies of binding consistent with relative sweetness. They are not accessible to sweet proteins which, however, can bind to a secondary site. Our models are consistent with most experimental observation on sweet taste, including sweetness synergy, and can help to design new sweeteners.