While Cockburn and colleagues (2012) speculate, if the four DENV serotypes bind to the same receptor, they have already identified a potential common binding site within the E protein for such a receptor interaction. disease following a secondary illness of DENV-immune individuals is incompletely recognized and may involve both arms of the adaptive immune response (Rothman, 2011). DENV-reactive antibodies are thought to contribute to not only safety from illness but also to exacerbated Isosilybin A disease following secondary infections. Antibody-dependent enhancement of infection identifies the more efficient illness of Fc-receptor-expressing cells in the presence of DENV-reactive antibodies and may contribute to severe disease (Kliks et al., 1989). While vaccines that protect against DENV are urgently needed, their development is definitely complicated by a requirement to simultaneously protect against all four serotypes of DENV (Whitehead et al., 2007). Therefore, understanding the molecular basis for the acknowledgement of DENV by homologous and cross-reactive antibodies is critical for understanding Isosilybin A Pou5f1 factors that contribute to pathogenesis. The envelope (E) protein is an elongated three website structure integrated into disease particles that orchestrates the attachment and access of virions into cells (Mukhopadhyay et al., 2005). The majority of anti-flavivirus neutralizing antibodies identify epitopes contained within or between the three domains of the E protein (Pierson et al., 2008). In this problem of em Structure /em , Cockburn and colleagues (2012) present fascinating fresh structural insights into the acknowledgement of DENV by a murine Isosilybin A monoclonal antibody (mAb) capable of neutralizing all four serotypes of DENV. mAb 4E11 is definitely a well-characterized cross-reactive murine mAb raised against DENV1 that binds website III (E-DIII) of the E protein. Biochemical analysis of the binding of this mAb to recombinant variants of E-DIII of DENV1 recognized nine residues that significantly impact antibody acknowledgement (Lisova et Isosilybin A al., 2007). These essential residues map to the A- and G- strands that form the edge of E-DIII -sandwich and have been shown to be involved the acknowledgement of many group-reactive anti-flavivirus antibodies (Sukupolvi-Petty et al., 2007). The structure of 4E11 in complex with E-DIII from all four serotypes of DENV right now described stretches these studies by defining how variance in the 4E11 epitope among DENV strains modulates antibody binding and neutralization. 4E11 binds each DENV serotype in a similar manner via relationships with residues within the Aand G-strands surrounding a hydrophobic core region of E-DIII. These studies determine the conserved residues required for cross-reactivity among DENV strains as well as the contribution of more variable side chains toward the designated difference in binding affinity among DENV serotypes. Of significant interest, the relative position of 4E11 in complex with E-DIII from each DENV serotype shows the antibody shifts position within the A-strand epitope to accommodate the nonconserved residues among DENV strains. This increases the intriguing probability that subtle variations in the angle of antibody engagement of an epitope may translate into substantial variations in the connection of undamaged antibody molecules with the disease particle and in what figures. On adult DENV Isosilybin A virions, 180 E proteins are arranged as rafts of antiparallel dimers structured in an unusual herringbone pattern (Mukhopadhyay et al., 2005). This dense set up imposes steric constraints for antibody acknowledgement on the undamaged virion (Pierson et al., 2008). The A-strand epitope identified by mAb 4E11 is not predicted to be accessible within the adult virion. The distal end of E website II (E-DII) encodes a highly conserved hydrophobic fusion loop that is required for viral membrane fusion. On adult virions, the fusion loop packs into the hydrophobic pocket adjacent to the A-strand of.