Mutations of an antibody binding energy hot spot on domain III of the dengue 2 envelope glycoprotein exploited for neutralization escape |
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| Authors: | Gregory D. Gromowski Michael S. Diamond J. Ching Lee Trevor J. Pitcher |
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| Affiliation: | a Department of Pathology, Sealy Center for Vaccine Development, Center for Biodefense and Emerging Infectious Diseases, and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-0609, USAb Department of Biochemistry & Molecular Biology, Sealy Center for Vaccine Development, Center for Biodefense and Emerging Infectious Diseases, and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-0609, USAc Sealy Center for Structural Biology and Molecular Biophysics, Center for Biodefense and Emerging Infectious Diseases, and Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555-0609, USAd Arboviral Diseases Branch, Division of Vector-Borne Infectious Diseases, Centers for Disease Control, 3150 Rampart Road, Fort Collins, CO 80521, USAe Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USAf Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110, USAg Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO 63110, USA |
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| Abstract: | Previous crystallographic studies have identified a total of 11 DENV-2 envelope protein domain III (ED3) residues (K305, F306, K307, V308, V309, K310, I312, Q325, P364, K388, and N390) that interacted, through both side- and main-chain contacts, with the Fab of a dengue virus (DENV) subcomplex-specific neutralizing monoclonal antibody (MAb) 1A1D-2 (Lok et al., 2008). Here, we used DENV-2 recombinant ED3 mutants of the MAb 1A1D-2 structural epitope residues to determine the functional epitope of this MAb. The side-chains of residues K307, K310 and I312 were determined to be functionally critical for MAb binding, and thus constitute a hot spot of binding energy for MAb 1A1D-2 on the DENV-2 ED3. Overall, these findings demonstrate that only a subset of the amino acid residue side-chains within the structural epitope of MAb 1A1D-2 define a functional epitope on the DENV-2 ED3 that is essential for MAb binding and neutralization escape. |
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| Keywords: | Dengue Envelope protein domain 3 Neutralization Monoclonal antibodies |
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