Three dimensional on top view of the TAS1R3 heptahelical domain binding pocket model. The binding pocket is docked with NHDC (A), lactisole (B), and cyclamate (C). Intra- and extra cellular loops are removed and the helices are directly connected. The transmembrane segments (TM1–TM7) are denoted in orange. Important residues are labeled in Ballesteros-Weinstein nomenclature in addition to the one letter amino acid code. Amino acids that influence the activation of the sweet receptor by NHDC are shown as spheres. The size of the spheres corresponds to the size of the side chain. The spheres are colored according to their pharmacophoric properties. Hydrophobic amino acids (F, P, M, A, L, I, G, V, W) cyan, H-donor/acceptor (Y, T, S, H, C, N, Q) magenta, H-bond donors with a positive charge (R) blue. Possible H-bond interactions are presented as dotted lines The color of the dotted lines indicate the energy of a H-bond, blue indicates an energy of -0.3–0.6 kcal/Mol, magenta: -0.6–1.2 kcal/Mol, red: -1.2–2.4 kcal/Mol. C atoms of NHDC are displayed in white and oxygen in red. Amino acid positions printed in red refer to residues emerged from the first round of mutational analysis and have been used as anchor points. Amino acid positions printed in grey were predicted from the model to influence receptor activation by NHDC and have been verified by mutational analysis.