Lactisole Interacts with the Transmembrane Domains of Human T1R3 to Inhibit Sweet Taste

• Published in: The Journal of biological chemistry 2005-04, Vol.280 (15), p.15238-15246
• Main Authors: Jiang, Peihua, Cui, Meng, Zhao, Baohua, Liu, Zhan, Snyder, Lenore A., Benard, Lumie M.J., Osman, Roman, Margolskee, Robert F., Max, Marianna
• Format: Article
• Language: English
• Subjects: Alanine - chemistry; Animals; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Binding Sites; Cell Line; Cell Membrane - metabolism; Cysteine - chemistry; Dose-Response Relationship, Drug; Humans; Ligands; Mice; Models, Chemical; Models, Molecular; Mutation; Point Mutation; Primates; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Recombinant Fusion Proteins - chemistry; Taste; Tryptophan - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M414287200

The detection of sweet-tasting compounds is mediated in large part by a heterodimeric receptor comprised of T1R2+T1R3. Lactisole, a broad-acting sweet antagonist, suppresses the sweet taste of sugars, protein sweeteners, and artificial sweeteners. Lactisole's inhibitory effect is specific to humans and other primates; lactisole does not affect responses to sweet compounds in rodents. By heterologously expressing interspecies combinations of T1R2+T1R3, we have determined that the target for lactisole's action is human T1R3. From studies with mouse/human chimeras of T1R3, we determined that the molecular basis for sensitivity to lactisole depends on only a few residues within the transmembrane region of human T1R3. Alanine substitution of residues in the transmembrane region of human T1R3 revealed 4 key residues required for sensitivity to lactisole. In our model of T1R3's seven transmembrane helices, lactisole is predicted to dock to a binding pocket within the transmembrane region that includes these 4 key residues.