Structure of dengue virus envelope protein after membrane fusion.
Dengue virus enters a host cell when the viral envelope glycoprotein, E, binds a receptor and responds by rearrangement to the reduced pH of an endosome. The conformational change induces fusion of viral and host-cell membranes. A three-dimensional structure of the soluble E ectodomain (sE) in its trimeric, postfusion state reveals striking differences from the dimeric, prefusion form. The elongated trimer bears three "fusion loops" at one end, to insert into the host-cell membrane. Their structure allows us to model directly how these fusion loops interact with a lipid bilayer. The protein folds back on itself, directing its carboxy terminus towards the fusion loops. We propose a fusion mechanism driven by essentially irreversible conformational changes in E and facilitated by fusion-loop insertion into the outer bilayer leaflet. Specific features of the folded-back structure suggest strategies for inhibiting flavivirus entry. Nature 427, 313-319.
Crystal Structure of Dengue virus capsid protein E.
Dengue virus is an emerging global health threat. Its major envelope glycoprotein, E, mediates viral attachment and entry by membrane fusion. A crystal structure of the soluble ectodomain of E from dengue virus type 2 reveals a hydrophobic pocket lined by residues that influence the pH threshold for fusion. The pocket, which accepts a hydrophobic ligand, opens and closes through a conformational shift in a beta-hairpin at the interface between two domains. These features point to a structural pathway for the fusion-activating transition and suggest a strategy for finding small-molecule inhibitors of dengue and other flaviviruses. See our paper and PDB coordinates 1OKE and 1OAN.
Atomic Model of Human Papillomavirus.
Papillomaviruses propagate in differentiating skin cells, and certain types are responsible for the onset of cervical cancer. We have combined image reconstructions from electron cryomicroscopy (cryoEM) of bovine papillomavirus at 13 A resolution with coordinates from the crystal structure of small virus-like particles of the human papillomavirus type 16 L1 protein to generate the first atomic model of a papillomavirus. Our model shows that papilloma- and polyomaviruses have a conserved capsid architecture. Most of the C-terminal arm, which has been rebuilt in our model, is exposed on the viral surface and is likely to have a role in infection and in immunogenicity (see our paper and PDB coordinates 1L0T).