Selected article for: "antigenic domain and design site"

Author: Brian G. Pierce; Zhen-Yong Keck; Ruixue Wang; Patrick Lau; Kyle Garagusi; Khadija Elkholy; Eric A. Toth; Richard A. Urbanowicz; Johnathan D. Guest; Pragati Agnihotri; Melissa C. Kerzic; Alexander Marin; Alexander K. Andrianov; Jonathan K. Ball; Roy A. Mariuzza; Thomas R. Fuerst; Steven K.H. Foung
Title: Structure-based design of hepatitis C virus E2 glycoprotein improves serum binding and cross-neutralization
  • Document date: 2020_4_17
  • ID: b6to1v4u_38
    Snippet: The designed substitution H445P, which was generated to preferentially adopt the bnAb-bound form in a portion of E2 antigenic domain D that exhibits structural variability (31), showed the greatest level of success, both with regard to improvements in serum binding to homologous and heterologous HCVpp, as well as HCVpp neutralization of heterologous HCVpp. This design lies within a supersite of E2 associated with many broadly neutralizing antibod.....
    Document: The designed substitution H445P, which was generated to preferentially adopt the bnAb-bound form in a portion of E2 antigenic domain D that exhibits structural variability (31), showed the greatest level of success, both with regard to improvements in serum binding to homologous and heterologous HCVpp, as well as HCVpp neutralization of heterologous HCVpp. This design lies within a supersite of E2 associated with many broadly neutralizing antibodies (5, 6, 44, 45) , and through biophysical characterization and molecular dynamics simulation experiments, others have found that this region is likely quite flexible (27, 46), providing a rationale for stabilizing key residues to engage and elicit bNAbs. Interestingly, a residue adjacent to the site of this design appears to be functionally important, with the Q444R substitution restoring viral infectivity in the context of an HCVpp with a domain E "glycan shift" substitution, N417S (8) . The design strategy of utilizing proline residue substitutions to stabilize conformations of viral glycoproteins has been successful for HIV Env (47), respiratory syncytial virus (RSV) F (48), MERS coronavirus spike (49) , and recently, the novel coronavirus (SARS-CoV-2) spike (50) . The data from this study suggest that this approach is also useful in the context of HCV E2, and possibly E1E2.

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