2024/01/01 by Jordan, Christina, Hayashi, Taiki, Löbbert, Arnelle +12
Biochemistry, Genetics and Molecular Biology · #540 #Carbohydrates #Escherichia coli research studies #Glycosylation and Glycoproteins Research #Inhibitors #Ligands #Noncovalent interactions #Post-translational modification #Vibrio bacteria research studies
paper · doi:10.15488/20039
openalex publication_date 2024/01/01 · openalex created_date 2025/11/20 · openalex updated_date 2026/07/01
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.