Structural studies of viral membrane fusion proteins suggest that a "trimer
-of-hairpins" motif plays a critical role in the membrane fusion process of
many enveloped viruses. In this motif, a coiled coil (formed by homotrimer
ic association of the N-terminal regions of the protein) is surrounded by t
hree C-terminal regions that pack against the coiled coil in an oblique ant
iparallel manner. The resulting trimer-of-hairpins structure serves to brin
g the viral and cellular membranes together for fusion, LEARNCOIL-VMF, a co
mputational program developed to recognize coiled coil-like regions that fo
rm the trimer-of-hairpins motif, predicts these regions in the membrane fus
ion protein of the Visna virus. Peptides corresponding to the computational
ly identified sequences were synthesized, and the soluble core of the Visna
membrane fusion protein was reconstituted in solution. Its crystal structu
re at 1.5-Angstrom resolution demonstrates that a trimer-of-hairpins struct
ure is formed. Remarkably, despite less than 23% sequence identity, the ect
odomains in Visna and HIV-1 envelope glycoproteins show detailed structural
conservation, especially within the area of a hydrophobic pocket in the ce
ntral coiled coil currently being targeted for the development of new anti-
HIV drugs.