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High-Resolution Crystal Structures Elucidate the Molecular Basis of Cholera Blood Group Dependence.

ABSTRACT: Cholera is the prime example of blood-group-dependent diseases, with individuals of blood group O experiencing the most severe symptoms. The cholera toxin is the main suspect to cause this relationship. We report the high-resolution crystal structures (1.1-1.6 Å) of the native cholera toxin B-pentamer for both classical and El Tor biotypes, in complexes with relevant blood group determinants and a fragment of its primary receptor, the GM1 ganglioside. The blood group A determinant binds in the opposite orientation compared to previously published structures of the cholera toxin, whereas the blood group H determinant, characteristic of blood group O, binds in both orientations. H-determinants bind with higher affinity than A-determinants, as shown by surface plasmon resonance. Together, these findings suggest why blood group O is a risk factor for severe cholera.

SUBMITTER: Heggelund JE

PROVIDER: S-EPMC4833353 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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High-Resolution Crystal Structures Elucidate the Molecular Basis of Cholera Blood Group Dependence.

Heggelund Julie Elisabeth JE Burschowsky Daniel D Bjørnestad Victoria Ariel VA Hodnik Vesna V Anderluh Gregor G Krengel Ute U

PLoS pathogens 20160415 4

Cholera is the prime example of blood-group-dependent diseases, with individuals of blood group O experiencing the most severe symptoms. The cholera toxin is the main suspect to cause this relationship. We report the high-resolution crystal structures (1.1-1.6 Å) of the native cholera toxin B-pentamer for both classical and El Tor biotypes, in complexes with relevant blood group determinants and a fragment of its primary receptor, the GM1 ganglioside. The blood group A determinant binds in the o ...[more]

PMID: 27082955

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Project description:Cholera is caused by Vibrio cholerae and is an example of a blood-group-dependent disease. Recent studies suggest that the receptor-binding B subunit of the cholera toxin (CT) binds histo-blood group antigens at a secondary binding site. Herein, we studied the conformational dynamics of Lewis Y (LeY) oligosaccharides, H-tetrasaccharides and A-pentasaccharides, in aqueous solution by conducting accelerated molecular dynamics (aMD) simulations. The flexible nature of both oligosaccharides was displayed in aMD simulations. Furthermore, aMD simulations revealed that for both oligosaccharides in the free form, 4C1 and 1C4 puckers were sampled for all but GalNAc monosaccharides, while either the 4C1 (GlcNAc, Gal, GalNAc) or 1C4 (Fuc2, Fuc3) pucker was sampled in the CT-bound forms. In aMD, the complete transition from the 4C1 to 1C4 pucker was sampled for GlcNAc and Gal in both oligosaccharides. Further, we have observed a transition from the open to closed conformer in the case of A-pentasaccharide, while H-tetrasaccharide remains in the open conformation throughout the simulation. Both oligosaccharides adopted an open conformation in the CT binding site. Moreover, we have investigated the molecular basis of recognition of LeY oligosaccharides by the B subunit of the cholera toxin of classical and El Tor biotypes using the molecular mechanics generalized Born surface area (MM/GBSA) scheme. The O blood group determinant, H-tetrasaccharide, exhibits a stronger affinity to both biotypes compared to the A blood group determinant, A-pentasaccharide, which agrees with the experimental data. The difference in binding free energy between O and A blood group determinants mainly arises due to the increased entropic cost and desolvation energy in the case of A-pentasaccharide compared to that of H-tetrasaccharide. Our study also reveals that the terminal Fuc3 contributes most to the binding free energy compared to other carbohydrate residues as it forms multiple hydrogen bonds with CT. Overall, our study might help in designing glycomimetic drugs targeting the cholera toxin.

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High-Resolution Crystal Structures Elucidate the Molecular Basis of Cholera Blood Group Dependence.

Publications

High-Resolution Crystal Structures Elucidate the Molecular Basis of Cholera Blood Group Dependence.

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