Details
| Original language | English |
|---|---|
| Pages (from-to) | 1481-1489 |
| Number of pages | 9 |
| Journal | ACS Central Science |
| Volume | 10 |
| Issue number | 8 |
| Early online date | 12 Jul 2024 |
| Publication status | Published - 28 Aug 2024 |
Abstract
Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from Vibrio cholerae: this is one of the strongest protein-carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB5), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (Oδ-H → Fδ-) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB5 with native GM1, the GM1 carbohydrate epitope, and meta-mononitrophenyl-α-galactoside (MNPG) revealed a trend that fully supports the importance of this key interaction. These NMR data suggest that F-GM1 binds in a closely similar conformation as native GM1. Crystallographic analyses of the complex also confirm that the OH → F bioisosteric exchange at C2 of the terminal galactose induces a ring conformation that eliminates key hydrogen bonds: these interactions are compensated for by inter- and intramolecular fluorine-specific interactions.
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
- Chemical Engineering(all)
- General Chemical Engineering
Sustainable Development Goals
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In: ACS Central Science, Vol. 10, No. 8, 28.08.2024, p. 1481-1489.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine
AU - Jordan, Christina
AU - Hayashi, Taiki
AU - Lobbert, Arnelle
AU - Fan, Jingran
AU - Teschers, Charlotte S.
AU - Siebold, Kathrin
AU - Aufiero, Marialuisa
AU - Pape, Felix
AU - Campbell, Emma
AU - Axer, Alexander
AU - Bussmann, Kathrin
AU - Bergander, Klaus
AU - Kohnke, Jesko
AU - Gossert, Alvar D.
AU - Gilmour, Ryan
N1 - Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.
PY - 2024/8/28
Y1 - 2024/8/28
N2 - Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from Vibrio cholerae: this is one of the strongest protein-carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB5), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (Oδ-H → Fδ-) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB5 with native GM1, the GM1 carbohydrate epitope, and meta-mononitrophenyl-α-galactoside (MNPG) revealed a trend that fully supports the importance of this key interaction. These NMR data suggest that F-GM1 binds in a closely similar conformation as native GM1. Crystallographic analyses of the complex also confirm that the OH → F bioisosteric exchange at C2 of the terminal galactose induces a ring conformation that eliminates key hydrogen bonds: these interactions are compensated for by inter- and intramolecular fluorine-specific interactions.
AB - Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from Vibrio cholerae: this is one of the strongest protein-carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB5), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (Oδ-H → Fδ-) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB5 with native GM1, the GM1 carbohydrate epitope, and meta-mononitrophenyl-α-galactoside (MNPG) revealed a trend that fully supports the importance of this key interaction. These NMR data suggest that F-GM1 binds in a closely similar conformation as native GM1. Crystallographic analyses of the complex also confirm that the OH → F bioisosteric exchange at C2 of the terminal galactose induces a ring conformation that eliminates key hydrogen bonds: these interactions are compensated for by inter- and intramolecular fluorine-specific interactions.
UR - http://www.scopus.com/inward/record.url?scp=85198556660&partnerID=8YFLogxK
U2 - 10.1021/acscentsci.4c00622
DO - 10.1021/acscentsci.4c00622
M3 - Article
AN - SCOPUS:85198556660
VL - 10
SP - 1481
EP - 1489
JO - ACS Central Science
JF - ACS Central Science
SN - 2374-7943
IS - 8
ER -