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Structures of Hepatitis B Virus Cores Presenting a Model Epitope and Their Complexes with Antibodies

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      Abstract

      The core shell of hepatitis B virus is a potent immune stimulator, giving a strong neutralizing immune response to foreign epitopes inserted at the immunodominant region, located at the tips of spikes on the exterior of the shell. Here, we analyze structures of core shells with a model epitope inserted at two alternative positions in the immunodominant region. Recombinantly expressed core protein assembles into T = 3 and T = 4 icosahedral shells, and atomic coordinates are available for the T = 4 shell. Since the modified protein assembles predominantly into T = 3 shells, a quasi-atomic model of the native T = 3 shell was made. The spikes in this T = 3 structure resemble those in T = 4 shells crystallized from expressed protein. However, the spikes in the modified shells exhibit an altered conformation, similar to the DNA containing shells in virions. Both constructs allow full access of antibodies to the foreign epitope, DPAFR from the preS1 region of hepatitis B virus surface antigen. However, one induces a 10-fold weaker immune response when injected into mice. In this construct, the epitope is less constrained by the flanking linker regions and is positioned so that the symmetry of the shell causes pairs of epitopes to come close enough to interfere with one another. In the other construct, the epitope mimics the native epitope conformation and position. The interaction of native core shells with an antibody specific to the immunodominant epitope is compared to the constructs with an antibody against the foreign epitope. Our findings have implications for the design of vaccines based on virus-like particles.

      Abstract

      Graphical AbstractHighlights► The HBV core shell is highly immunogenic and is being used as a vaccine carrier. ► Insertion of model epitopes into the immunodominant region changes the structure. ► Alternative positions of an epitope give different structures and immunogenicity. ► The structural differences lead to different labeling with antibody fragments. ► We conclude that three‐dimensional structural analysis will be important in vaccine design.

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      Most cited references 56

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      The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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        The CCP4 suite: programs for protein crystallography.

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        The CCP4 (Collaborative Computational Project, number 4) program suite is a collection of programs and associated data and subroutine libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims and so there may be more than one program to cover each function. The programs are written mainly in standard Fortran77. They are from a wide variety of sources but are connected by standard data file formats. The package has been ported to all the major platforms under both Unix and VMS. The suite is distributed by anonymous ftp from Daresbury Laboratory and is widely used throughout the world.
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          SPIDER and WEB: processing and visualization of images in 3D electron microscopy and related fields.

          The SPIDER system has evolved into a comprehensive tool set for image processing, making use of modern graphics interfacing in the VMS and UNIX environment. SPIDER and WEB handle the complementary tasks of batch processing and visualization of the results. The emphasis of the SPIDER system remains in the area of single particle averaging and reconstruction, although a variety of other application areas have been added. Novel features are a suite of operations relating to the determination, modeling, and correction of the contrast transfer function and the availability of the entire documentation in hypertext format.
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            Author and article information

            Affiliations
            [1 ]MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
            [2 ]Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK
            [3 ]Latvian Biomedical Research and Study Centre, 1 Ratsupites Street, LV-1067 Riga, Latvia
            Author notes
            [* ]Corresponding author. Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. Alan.Roseman@ 123456manchester.ac.uk
            [1]

            Present addresses: O. Borschukova, 30 Gardner Road, Apt. 3H, Brookline, MA 02445, USA; J. A. Berriman, 51 Oakhill Road, Putney, London SW15 2QJ, UK.

            Contributors
            Journal
            J Mol Biol
            J. Mol. Biol
            Journal of Molecular Biology
            Elsevier
            0022-2836
            1089-8638
            12 October 2012
            12 October 2012
            : 423
            : 1
            : 63-78
            22750730
            3465560
            YJMBI63735
            10.1016/j.jmb.2012.06.032
            © 2012 Elsevier Ltd.

            This document may be redistributed and reused, subject to certain conditions.

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