The binding site for neohesperidin dihydrochalcone at the human sweet taste receptor

Winnig, Marcel; Bufe, Bernd; Kratochwil, Nicole A.; Slack, Jay P.; Meyerhof, Wolfgang
January 2007
BMC Structural Biology;2007, Vol. 7, p66
Academic Journal
Background: Differences in sweet taste perception among species depend on structural variations of the sweet taste receptor. The commercially used isovanillyl sweetener neohesperidin dihydrochalcone activates the human but not the rat sweet receptor TAS1R2+TAS1R3. Analysis of interspecies combinations and chimeras of rat and human TAS1R2+TAS1R3 suggested that the heptahelical domain of human TAS1R3 is crucial for the activation of the sweet receptor by neohesperidin dihydrochalcone. Results: By mutational analysis combined with functional studies and molecular modeling we identified a set of different amino acid residues within the heptahelical domain of human TAS1R3 that forms the neohesperidin dihydrochalcone binding pocket. Sixteen amino acid residues in the transmembrane domains 2 to 7 and one in the extracellular loop 2 of hTAS1R3 influenced the receptor's response to neohesperidin dihydrochalcone. Some of these seventeen residues are also part of the binding sites for the sweetener cyclamate or the sweet taste inhibitor lactisole. In line with this observation, lactisole inhibited activation of the sweet receptor by neohesperidin dihydrochalcone and cyclamate competitively, whereas receptor activation by aspartame, a sweetener known to bind to the N-terminal domain of TAS1R2, was allosterically inhibited. Seven of the amino acid positions crucial for activation of hTAS1R2+hTAS1R3 by neohesperidin dihydrochalcone are thought to play a role in the binding of allosteric modulators of other class C GPCRs, further supporting our model of the neohesperidin dihydrochalcone pharmacophore. Conclusion: From our data we conclude that we identified the neohesperidin dihydrochalcone binding site at the human sweet taste receptor, which overlaps with those for the sweetener cyclamate and the sweet taste inhibitor lactisole. This readily delivers a molecular explanation of our finding that lactisole is a competitive inhibitor of the receptor activation by neohesperidin dihydrochalcone and cyclamate. Some of the amino acid positions crucial for activation of hTAS1R2+hTAS1R3 by neohesperidin dihydrochalcone are involved in the binding of allosteric modulators in other class C GPCRs, suggesting a general role of these amino acid positions in allosterism and pointing to a common architecture of the heptahelical domains of class C GPCRs.


Related Articles

  • Synergism among Ternary Mixtures of Fourteen Sweeteners. Schiffman, Susan S.; Sattely-Miller, Elizabeth A.; Graham, Brevick G.; Booth, Barbara J.; Gibes, Kernon M. // Chemical Senses;Apr2000, Vol. 25 Issue 2, p131 

    The purpose of the present study was to determine the degree of synergism of sweet taste among ternary mixtures of 14 sweeteners. A trained panel evaluated ternary mixtures of 14 sweeteners varying in chemical structure and type. The ternary mixtures that were tested were limited to those in...

  • From Aldrovandi's “Homuncio” (1592) to Buffon's girl (1749) and the “Wart Man” of Tilesius (1793): antique illustrations of mosaicism in neurofibromatosis? Ruggieri, M.; Polizzi, A. // Journal of Medical Genetics;Mar2003, Vol. 40 Issue 3, p227 

    Examines antique illustrations of mosaicism in neurofibromatosis. Occurence of dominant disorders; Reflection of heterozygosity for a postzygotic mutation; Limitation of segmental lesions.

  • Effect of Repeated Presentation on Sweetness Intensity of Binary and Ternary Mixtures of Sweeteners. Schiffman, Susan S.; Sattely-Miller, Elizabeth A.; Graham, Brevick G.; Zervakis, Jennifer; Butchko, Harriett H.; Stargel, W. Wayne // Chemical Senses;Mar2003, Vol. 28 Issue 3, p219 

    The purpose of the present study was to determine the effect of repeated presentation of the same sweet stimulus on sweetness intensity ratings. The sweet stimuli tested in this study were binary and ternary blends of 14 sweeteners that varied widely in chemical structure. A trained panel...

  • The new sugar alternatives: are they safe? Broihier, Kitty // Shape;Feb2003, Vol. 22 Issue 6, p117 

    Presents information on artificial sweeteners and their health risks, if any. Form of availability, sweetness and uses of sweeteners Agave, Neotame, Stevia and Sucralose; Health concern owing to the use of Stevia.

  • Your Brain on Bubbles.  // Prevention;Jan2014, Vol. 66 Issue 1, p24 

    The article informs that according to a study published in the journal "Gastroenterology," brain regions in the drinkers of sugar-free and sugary sodas detect same sweetness, because of the carbon dioxide, which makes sugar and artificial sweeteners taste similar.

  • Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. Wada, Taizo; Konno, Akihiro; Schurman, Shepherd H.; Garabedian, Elizabeth K.; Anderson, Stacie M.; Kirby, Martha; Nelson, David L.; Candotti, Fabio // Journal of Clinical Investigation;5/1/2003, Vol. 111 Issue 9, p1389 

    Describes somatic mosaicism in two brothers affected with Wiskott-Aldrich syndromes (WAS). Original mutation causing disease in the family; Factor which abrogated the effects of the original mutation and restored the WAS protein reading frame; Evidence for potential beneficial outcomes of...

  • Mosaicism for ATP2A2 Mutations Causes Segmental Darier's Disease. Sakuntabhai, Anavaj; Dhitavat, Jittima; Burge, Susan; Hovnanian, Alain // Journal of Investigative Dermatology;Dec2000, Vol. 115 Issue 6, p1144 

    Summary Epidermal naevi are localized malformations of the epidermis consisting of verrucoid scaly papules and plaques following Blaschko's lines. Genetic mosaicism has been proposed to underlie the development of linear epidermal naevi. Rarely, epidermal naevi show acantholytic histology...

  • PAX2 mutations in renal—coloboma syndrome: mutational hotspot and germline mosaicism. Amiel, Jeanne; Audollent, Sophie; Joly, Dominique; Dureau, Pascal; Salomon, Rémi; Tellier, Anne-Lorraine; Augé, Joelle; Bouissou, François; Antignac, Corinne; Gubler, Marie-Claire; Eccles, Michel R; Munnich, Arnold; Vekemans, Michel; Lyonnet, Stanislas; Attié-Bitach, Tania // European Journal of Human Genetics;Nov2000, Vol. 8 Issue 11, p820 

    The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant disorder caused by PAX2 gene mutations. We screened the entire coding sequence of the PAX2 gene for mutations in nine patients with RCS. We found five heterozygous PAX2 gene mutations: a dinucleotide insertion (2G) at...

  • Postzygotic mutation and germline mosaicism in the otopalatodigital syndrome spectrum disorders. Robertson, Stephen P; Thompson, Sarah; Morgan, Timothy; Holder-Espinasse, Muriel; Martinot-Duquenoy, Véronique; Wilkie, Andrew O M; Manouvrier-Hanu, Sylvie // European Journal of Human Genetics;May2006, Vol. 14 Issue 5, p549 

    The otopalatodigital syndrome (OPD) spectrum disorders are a heterogeneous group of skeletal dysplasias caused by mutations in the X-linked gene, FLNA. All OPD spectrum disorders (otopalatodigital syndromes types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome) exhibit...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics