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Crystal Structure of Botulinum Neurotoxin Type A in Complex with the Cell Surface Co-Receptor GT1b—Insight into the Toxin–Neuron Interaction

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      Abstract

      Botulinum neurotoxins have a very high affinity and specificity for their target cells requiring two different co-receptors located on the neuronal cell surface. Different toxin serotypes have different protein receptors; yet, most share a common ganglioside co-receptor, GT1b. We determined the crystal structure of the botulinum neurotoxin serotype A binding domain (residues 873–1297) alone and in complex with a GT1b analog at 1.7 Å and 1.6 Å, respectively. The ganglioside GT1b forms several key hydrogen bonds to conserved residues and binds in a shallow groove lined by Tryptophan 1266. GT1b binding does not induce any large structural changes in the toxin; therefore, it is unlikely that allosteric effects play a major role in the dual receptor recognition. Together with the previously published structures of botulinum neurotoxin serotype B in complex with its protein co-receptor, we can now generate a detailed model of botulinum neurotoxin's interaction with the neuronal cell surface. The two branches of the GT1b polysaccharide, together with the protein receptor site, impose strict geometric constraints on the mode of interaction with the membrane surface and strongly support a model where one end of the 100 Å long translocation domain helix bundle swing into contact with the membrane, initiating the membrane anchoring event.

      Author Summary

      Botulinum neurotoxins are the most toxic substances known and are classified as a category A bioterrorism agent. Ongoing work on the development of countermeasures for the neurotoxin has been limited by an incomplete understanding of the means by which the toxin enters the cell. Our study provides a detailed look at how the toxin binds its ganglioside co-receptor on the cell surface. Together with earlier work this generates a detailed description of how the toxin binds its two co-receptors to position it for entrance into the neuronal cell. This structural data provides critical new insight about the action of the botulinum neurotoxins that can be applied toward the development of agents to block toxin uptake in the digestive system and/or inhibit the binding of the toxin at the neuromuscular junction.

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      Most cited references 44

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            Author and article information

            Affiliations
            [1 ]Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America
            [2 ]Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida, Sakyo-ku, Kyoto, Japan
            The Rockefeller University, United States of America
            Author notes

            Conceived and designed the experiments: PS JD RCS. Performed the experiments: PS JD. Analyzed the data: PS RCS. Contributed reagents/materials/analysis tools: AI MK. Wrote the paper: PS RCS.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            August 2008
            August 2008
            15 August 2008
            : 4
            : 8
            2493045
            18704164
            08-PLPA-RA-0383R2
            10.1371/journal.ppat.1000129
            (Editor)
            Stenmark et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 10
            Categories
            Research Article
            Biochemistry/Biomacromolecule-Ligand Interactions
            Biochemistry/Experimental Biophysical Methods
            Infectious Diseases/Bacterial Infections
            Infectious Diseases/Infectious Diseases of the Nervous System

            Infectious disease & Microbiology

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