Abstract
Clostridium difficile TcdA is a large toxin that binds carbohydrates on intestinal epithelial cells. A 2-Å resolution cocrystal structure reveals two molecules of α-Gal-(1,3)-β-Gal-(1,4)-β-GlcNAcO(CH2)8CO2CH3 binding in an extended conformation to TcdA. Residues forming key contacts with the trisaccharides are conserved in all seven putative binding sites in TcdA, suggesting a mode of multivalent binding that may be exploited for the rational design of novel therapeutics.
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Acknowledgements
We thank I. Barrette-Ng for helpful discussions. This work was supported by the Alberta Ingenuity Centre for Carbohydrate Science (M.M.P. and K.K.-S.N.), the Canadian Institutes of Health Research (K.K.-S.N.) and the Alberta Heritage Foundation for Medical Research (AHFMR; to K.K.-S.N.). J.G.S.H. was supported by a fellowship from the Alberta Ingenuity Fund. M.R. was supported by the Slovenian research Agency (project J1-6456). Diffraction data were collected at beamline 8.3.1 of the Advanced Light Source (ALS) at Lawrence Berkeley Lab under an agreement with the Alberta Synchrotron Institute (ASI). The ALS is operated by the US Department of Energy and supported by the US National Institutes of Health. Beamline 8.3.1 was funded by the US National Science Foundation, the University of California and Henry Wheeler. The ASI synchrotron access program is supported by the Alberta Science and Research Authority and the AHFMR.
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Supplementary information
Supplementary Fig. 1
Difference electron density map (PDF 305 kb)
Supplementary Fig. 2
Model of the TcdA CRD showing the disposition of carbohydrate-binding sites. (PDF 278 kb)
Supplementary Table 1
Data collection and refinement statistics (PDF 73 kb)
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Greco, A., Ho, J., Lin, SJ. et al. Carbohydrate recognition by Clostridium difficile toxin A. Nat Struct Mol Biol 13, 460–461 (2006). https://doi.org/10.1038/nsmb1084
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DOI: https://doi.org/10.1038/nsmb1084
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