Lactisole interacts with the transmembrane domains of human T1R3 to inhibit sweet taste.
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.
Jiang
Peihua
P
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
Cui
Meng
M
Zhao
Baohua
B
Liu
Zhan
Z
Snyder
Lenore A
LA
Benard
Lumie M J
LM
Osman
Roman
R
Margolskee
Robert F
RF
Max
Marianna
M
D000409:Alanine / Q000737:chemistry; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013649:Taste; D014364:Tryptophan / Q000737:chemistry
D001555:Benzene Derivatives; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C431926:taste receptors, type 1; D014364:Tryptophan; D003545:Cysteine; D000409:Alanine; C495512:lactisole