Solution structure and antibody binding studies of the envelope protein domain III from the New York strain of West Nile virus

Abstract

The solution structure of domain III from the New York West Nile virus strain 385-99 (WN-rED3) has been determined by NMB methods. The West Nile domain III structure is a β-barrel structure formed from seven anti-parallel β-strands in two β-sheets. One anti-parallel β-sheet consists of β-strands β1 (Phe299-Asp307), β2 (Val 313-Tyr319), β4 (Arg354-Leu 355), and β5 (Lys370-Glu376) arranged so that β2 is flanked on either side by β1 and β5. The short β4 flanks the end of the remaining side of β5. The remaining anti-parallel β-sheet is formed from strands β3 (Ile340-Val 343), β6 (Gly380-Arg388), and β7 (Gln391-Lys399) arranged with β6 at the center. Residues implicated in antigenic differences between different West Nile virus strains (and other flaviviruses) and neutralization are located on the outer surface of the protein. Characterization of the binding of monoclonal antibodies to WN-rED3 mutants, which were identified through neutralization escape experiments, indicate that antibody neutralization directly correlates with binding affinities. These studies provide an insight into theoretical virus-receptor interaction points, structure of immunogenic determinants, and potential targets for antiviral agents against West Nile virus and highlight differences between West Nile virus and other flavivirus structures that may represent critical determinants of virulence.