Blog
About

27
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references 44

          • Record: found
          • Abstract: found
          • Article: not found

          Coot: model-building tools for molecular graphics.

          CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as 'Coot'.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Refinement of macromolecular structures by the maximum-likelihood method.

            This paper reviews the mathematical basis of maximum likelihood. The likelihood function for macromolecular structures is extended to include prior phase information and experimental standard uncertainties. The assumption that different parts of a structure might have different errors is considered. A method for estimating sigma(A) using 'free' reflections is described and its effects analysed. The derived equations have been implemented in the program REFMAC. This has been tested on several proteins at different stages of refinement (bacterial alpha-amylase, cytochrome c', cross-linked insulin and oligopeptide binding protein). The results derived using the maximum-likelihood residual are consistently better than those obtained from least-squares refinement.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions.

              The present paper describes the SSM algorithm of protein structure comparison in three dimensions, which includes an original procedure of matching graphs built on the protein's secondary-structure elements, followed by an iterative three-dimensional alignment of protein backbone Calpha atoms. The SSM results are compared with those obtained from other protein comparison servers, and the advantages and disadvantages of different scores that are used for structure recognition are discussed. A new score, balancing the r.m.s.d. and alignment length Nalign, is proposed. It is found that different servers agree reasonably well on the new score, while showing considerable differences in r.m.s.d. and Nalign.
                Bookmark

                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

                Comments

                Comment on this article