Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine

authored by: Christina Jordan, Taiki Hayashi, Arnelle Lobbert, Jingran Fan, Charlotte S. Teschers, Kathrin Siebold, Marialuisa Aufiero, Felix Pape, Emma Campbell, Alexander Axer, Kathrin Bussmann, Klaus Bergander, Jesko Kohnke, Alvar D. Gossert, Ryan Gilmour
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 (O^δ-H → F^δ-) 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.
Organisation(s): Institute of Food Chemistry
External Organisation(s): University of Münster
ETH Zurich
Type: Article
Journal: ACS Central Science
Volume: 10
Pages: 1481-1489
No. of pages: 9
ISSN: 2374-7943
Publication date: 28.08.2024
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: General Chemistry, General Chemical Engineering
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.1021/acscentsci.4c00622 (Access: Open)

BibTeX

@article{325d1ab0435d4304ba5da8c9d0f62903,
title = "Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine",
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.",
author = "Christina Jordan and Taiki Hayashi and Arnelle Lobbert and Jingran Fan and Teschers, {Charlotte S.} and Kathrin Siebold and Marialuisa Aufiero and Felix Pape and Emma Campbell and Alexander Axer and Kathrin Bussmann and Klaus Bergander and Jesko Kohnke and Gossert, {Alvar D.} and Ryan Gilmour",
note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Published by American Chemical Society.",
year = "2024",
month = aug,
day = "28",
doi = "10.1021/acscentsci.4c00622",
language = "English",
volume = "10",
pages = "1481--1489",
journal = "ACS Central Science",
issn = "2374-7943",
publisher = "American Chemical Society",
number = "8",
}