The Human Sweet Taste Receptor

The sweet taste receptor (SR) is a G protein-coupled receptor (GPCR) that is similar to the dimeric mGluR1 rececptor. Both of these receptors are class C GPCRs, which includes other taste receptors, pheromone receptors, the calcium sensing receptor and the gamma-aminobutyric acid type B receptor. All of these GPCRs have a domain made up of seven transmembrane helices and a large extracellular domain comprising a Venus fly trap domain (VFTD) containing the binding site for ligands and a cysteine-rich domain.

There is currently no experimental structure available for the sweet taste receptor. However, as there are crystal structures available of the VFTD of mGluR1, homology models can be built of SR using these crystal structures as templates. One major structural differences between mGluR1 and SR is that the former is homodimeric whereas the latter is heterodimeric.

We have built a model of the SR using mGluR1 as a template (PDB code: 1EWK).
Homology modelling was carried out using Modeller in Accelrys Discovery Studio 2.5. T1R2 was built using chain A of 1EWK and T1R3 using chain B. The large insertions in T1R2 and T1R3 compared to the template were removed from the final model.

Our SR model is in an active conformation and contains two cavities that can host ligands: a smaller one in the closed protomer (chain A) and a larger one in the open protomer (chain B). We superimposed the SR model with the mGluR1 crystal structure based on the active site residues of mGluR1 that are conserved in the SR. We then used the glutamate ligands bound to mGluR1 to identify the possible active site residues in SR (all those within 5 Angstrom of the glutamate molecules). We then used the GOLD docking algorithm to dock low molecular weight sweet molecules into the active site of SR and identify the best scoring poses. Compounds less than 400 kDa were docked into both active sites whereas those greater than or equal to 400kDa were only docked into site B. This has been done for the base set of compounds stored in SuperSweet. Below shows Stevioside docked into the active site of the T1R3 protomer of the SR.

Homology model of the Sweet Taste Receptor (based on the Glutamate Receptor) with Stevioside docked into the active site of the T1R3 protomer.