Structural characterization of the human respiratory syncytial virus fusion protein core

Human respiratory syncytial virus (HRSV) is a major cause of a number of se vere respiratory diseases, including bronchiolitis and pneumonia, in infant s and young children. The HRSV F protein, a glycoprotein essential for vira l entry, is a primary target for vaccine and drug development Two heptad-re peat regions within the HRSV F sequence were predicted by the computer prog ram LEARN-COIL-VMF. These regions are thought to form trimer-of-hairpins-li ke structures, similar to those found in the fusion proteins of several env eloped viruses. The hairpin structure likely brings the viral and cellular membranes into close apposition, thereby facilitating membrane fusion and s ubsequent viral entry. Here, we show that peptides, denoted HR-N and HR-C, corresponding to the heptad-repeat regions from the N-terminal and C-termin al segments of the HRSV F protein, respectively, form a stable alpha -helic al trimer of heteradimers. The HRSV N/C complex was crystallized and its x- ray structure was determined at 2.3-Angstrom resolution. As anticipated, th e complex is a six-helix bundle in which the HR-N peptides form a three-str anded, central coiled coil, and the HR-C peptides pack in an antiparallel m anner into hydrophobic grooves on the coiled-coil surface. There is remarka ble structural similarity between the HRSV N/C complex and the fusion prote in core of other viruses, including HIV-1 gp41. In addition, earlier work h as shown that HRSV HR-C peptides, like the HIV-1 gp41 C peptides, inhibit v iral infection. Thus, drug discovery and vaccine development strategies aim ed at inhibiting viral entry by blocking hairpin formation may be applied t o the inhibition of HRSV.