The BLV crystal structure and our analysis of HTLV-1 and BLV envelope-mediated membrane fusion reveal an important role for electrostatic interactions in binding of the LHR to the grooves of the coiled coil. For both BLV and HTLV-1 a conserved basic residue in the second helical segment of the LHR interacts with the charged rim of a deep pocket lined by non-polar residues. For HTLV-1 the contribution of charge is enhanced by the interaction of an additional basic residue (Arg416) with the opposite rim of the pocket. Thus, while the insertion of non-polar residues into hydrophobic pockets likely drives the docking of the LHR with the coiled coil, we suggest that it is the electrostatic attraction and hydrogen bonding of charged side chains around these hydrophobic interactions that serves to ''cement'' the LHR in place and thereby establish the precise geometry and affinity of this interaction. In keeping with this view, substitution of these basic residues ablates envelope-mediated membrane fusion and dramatically impairs the inhibitory and coiled-coil-binding properties of LHR-based peptides [22] . Moreover, only one of these important basic residues is conserved in BLV compared to HTLV-1 and it is notable that the synthetic BLV LHR-mimetic is approximately 10-fold less potent than the corresponding inhibitor of HTLV-1 [17] . Examination of the electrostatic surfaces of BLV, HTLV, HIV and MoMLV coiled coils reveals, in each case, the presence of a pocket surrounded by charged residues, though the polarity of the charge and positioning along the groove is variable (Fig. 6 ). The importance of the pocket and surrounding charge to the assembly of the trimer-of-hairpins and the potency of C-helixbased mimetic peptides has been demonstrated for HIV [43, 44] , and taken with our findings for BLV and HTLV-1 suggest that such charged regions are critical to retroviral envelope-mediated membrane fusion in general. We suggest that structure-assisted design of small molecules to target these charge-surrounded pockets is a viable objective for anti-retroviral therapy.