Predicted Structure of Fully Activated Tas1R3/1R3' Homodimer Bound to G Protein and Natural Sugars: Structural Insights into G Protein Activation by a Class C Sweet Taste Homodimer with Natural Sugars.

The Tas1R3 G protein-coupled receptor constitutes the main component of sweet taste sensory response in humans via forming a heterodimer with Tas1R2 or a homodimer with Tas1R3. The Tas1R3/1R3' homodimer serves as a low-affinity sweet taste receptor, stimulating gustducin G protein (G) signaling in the presence of a high concentration of natural sugars. This provides an additional means to detect the taste of natural sugars, thereby differentiating the flavors between natural sugars and artificial sweeteners. We report here the predicted 3D structure of active state Tas1R3/1R3' homodimer complexed with heterotrimeric G and sucrose. We discovered that the G makes ionic anchors to intracellular loops 1 and 2 of Tas1R3 while the Gα-α5 helix engages the cytoplasmic region extensively through salt bridge and hydrophobic interactions. We show that in the activation of this complex the Venus flytrap domains of the homodimer undergo a remarkable twist up to ∼100° rotation around the vertical axis to adopt a closed-closed conformation while the intracellular region relaxes to an open-open conformation. We find that binding of sucrose to the homodimer stabilizes a preactivated conformation with a largely open intracellular region that recruits and activates the G. Upon activation, the Gα subunit spontaneously opens up the nucleotide-binding site, making nucleotide exchange facile for signaling. This activation of G promotes the interdomain twist of the Venus flytrap domains. These structures and transformations could potentially be a basis for the design of new sweeteners with higher activity and less unpleasant flavors.