Charge-surrounded pockets and electrostatic interactions with small ions modulate the activity of retroviral fusion proteins

Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure promotes entry of viruses into cells. here we present the structure of the bovine leukaemia virus transmembrane glycoprotein (tm) and identify a group of asparagine residues at the membrane-distal end of the trimer-of-hairpins that is strikingly conserved among divergent viruses. these asparagines are not essential for surface display of pre-fusogenic envelope. instead,substitution of these residues dramatically disrupts membrane fusion. our data indicate that,through electrostatic interactions with a chloride ion,the asparagine residues promote assembly and profoundly stabilize the fusion-active structures that are required for viral envelope-mediated membrane fusion. moreover,the blv tm structure also reveals a charge-surrounded hydrophobic pocket on the central coiled coil and interactions with basic residues that cluster around this pocket are critical to membrane fusion and form a target for peptide inhibitors of envelope function. charge-surrounded pockets and electrostatic interactions with small ions are common among class-1 fusion proteins,suggesting that small molecules that specifically target such motifs should prevent assembly of the trimer-of-hairpins and be of value as therapeutic inhibitors of viral entry. © 2011 lamb et al.