The likely conservation of position and orientation of HTLV-1 R422 in the trimer-of-hairpins allowed us to construct a model for the binding of the C-terminal segment of the HTLV-1 LHR to the coiled coil (Fig. 5D) . The model suggests that R422 could bind to a negatively charged ridge that is orientated across the groove between N-helices and that lies between the binding pockets for Leu413 and Leu419 and that R422 docks adjacent to R416. As such, four critical interactions between LHR side chains and the coiled coil are contained within a binding hotspot of ,16 Å x ,8 Å and disruption of these interactions profoundly impairs envelope-mediated membrane fusion.