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Cholera toxin B subunit in complex with fluorinated GM1
Structural highlights
FunctionCHTB_VIBCH The B subunit pentameric ring directs the A subunit to its target by binding to the GM1 gangliosides present on the surface of the intestinal epithelial cells. It can bind five GM1 gangliosides. It has no toxic activity by itself. Publication Abstract from PubMedCarbohydrates 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 (CTB(5)), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps. This process of molecular editing (O(delta-)H --> F(delta-)) strategically deletes the hydrogen bond donor while retaining the localized partial charge of the substituent. Comparison of the binding affinity of F-GM1/CTB(5) with native GM1, the GM1 carbohydrate epitope, and meta-mononitrophenyl-alpha-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. Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine.,Jordan C, Hayashi T, Lobbert A, Fan J, Teschers CS, Siebold K, Aufiero M, Pape F, Campbell E, Axer A, Bussmann K, Bergander K, Kohnke J, Gossert AD, Gilmour R ACS Cent Sci. 2024 Jul 12;10(8):1481-1489. doi: 10.1021/acscentsci.4c00622. , eCollection 2024 Aug 28. PMID:39220706[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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