Cocrystal Structures of NC6.8 Fab Identify Key Interactions for High Potency Sweetener Recognition: Implications for the Design of Synthetic Sweeteners
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- 作者：Kuppan Gokulan ; Sangeeta Khare ; Donald R. Ronning ; Scott D. Linthicum ; James C. Sacchettini ; and Bernhard Rupp
- 刊名：Biochemistry
- 出版年：2005
- 出版时间：July 26, 2005
- 年：2005
- 卷：44
- 期：29
- 页码：9889 - 9898
- 全文大小：561K
- 年卷期：v.44,no.29(July 26, 2005)
- ISSN：1520-4995
文摘
The crystal structures of the murine monoclonal IgG2b(
) antibody NC6.8 Fab fragmentcomplexed with high-potency sweetener compound SC45647 and nontasting high-affinity antagonist TEShave been determined. The crystal structures show how sweetener potency is fine-tuned by multipleinteractions between specific receptor residues and the functionally different groups of the sweeteners.Comparative analysis with the structure of NC6.8 complexed with the super-potency sweetener NC174reveals that although the same residues in the antigen binding pocket of NC6.8 interact with the zwitterionic,trisubstituted guanidinium sweeteners as well as TES, specific differences exist and provide guidance forthe design of new artificial sweeteners. In case of the nonsweetener TES, the interactions with the receptorare indirectly mediated through a hydrogen bonded water network, while the sweeteners bind with highaffinity directly to the receptor. The presence of a hydrophobic group interacting with multiple receptorresidues as a major determinant for sweet taste has been confirmed. The nature of the hydrophobic groupis likely a discriminator for super- versus high-potency sweeteners, which can be exploited in the designof new, highly potent sweetener compounds. Overall similarities and partial conservation of interactionsindicate that the NC6.8 Fab surrogate is representing crucial features of the T1R2 taste receptor VFTMbinding site.
) antibody NC6.8 Fab fragmentcomplexed with high-potency sweetener compound SC45647 and nontasting high-affinity antagonist TEShave been determined. The crystal structures show how sweetener potency is fine-tuned by multipleinteractions between specific receptor residues and the functionally different groups of the sweeteners.Comparative analysis with the structure of NC6.8 complexed with the super-potency sweetener NC174reveals that although the same residues in the antigen binding pocket of NC6.8 interact with the zwitterionic,trisubstituted guanidinium sweeteners as well as TES, specific differences exist and provide guidance forthe design of new artificial sweeteners. In case of the nonsweetener TES, the interactions with the receptorare indirectly mediated through a hydrogen bonded water network, while the sweeteners bind with highaffinity directly to the receptor. The presence of a hydrophobic group interacting with multiple receptorresidues as a major determinant for sweet taste has been confirmed. The nature of the hydrophobic groupis likely a discriminator for super- versus high-potency sweeteners, which can be exploited in the designof new, highly potent sweetener compounds. Overall similarities and partial conservation of interactionsindicate that the NC6.8 Fab surrogate is representing crucial features of the T1R2 taste receptor VFTMbinding site.