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Permanent link (DOI): https://doi.org/10.7939/R3R78622G

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Structural basis for antibody recognition in the receptor-binding domains of toxins A and B from Clostridium difficile Open Access

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Author or creator
Murase, Tomohiko
Eugenio, Luiz
Schorr, Melissa
Hussack, Greg
Tanha, Jamshid
Kitova, Elena N.
Klassen, John S.
Ng, Kenneth K. S.
Additional contributors
Subject/Keyword
Mass Spectrometry (MS)
Protein-Protein Interactions
X-ray Crystallography
Antibodies
Bacterial Toxins
Type of item
Journal Article (Published)
Language
English
Place
Time
Description
Clostridium difficile infection is a serious and highly prevalent nosocomial disease in which the two large, Rho-glucosylating toxins TcdA and TcdB are the main virulence factors. We report for the first time crystal structures revealing how neutralizing and non-neutralizing single-domain antibodies (sdAbs) recognize the receptor-binding domains (RBDs) of TcdA and TcdB. Surprisingly, the complexes formed by two neutralizing antibodies recognizing TcdA do not show direct interference with the previously identified carbohydrate-binding sites, suggesting that neutralization of toxin activity may be mediated by mechanisms distinct from steric blockage of receptor binding. A camelid sdAb complex also reveals the molecular structure of the TcdB RBD for the first time, facilitating the crystallization of a strongly negatively charged protein fragment that has resisted previous attempts at crystallization and structure determination. Electrospray ionization mass spectrometry measurements confirm the stoichiometries of sdAbs observed in the crystal structures. These studies indicate how key epitopes in the RBDs from TcdA and TcdB are recognized by sdAbs, providing molecular insights into toxin structure and function and providing for the first time a basis for the design of highly specific toxin-specific therapeutic and diagnostic agents.
Date created
2014
DOI
doi:10.7939/R3R78622G
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© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Citation for previous publication
Murase, T., Eugenio, L., Schorr, M., Hussack, G., Tanha, J., Kitova, E., Klassen, J., and Ng, K. (2014). Structural basis for antibody recognition in the receptor-binding domains of toxins A and B from Clostridium difficile. Journal of Biological Chemistry, 289(4), 2331-2343.
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