Here we show the structure of the post-fusion conformation of the BLV TM ectodomain and demonstrate that coordinated ions and a network of hydrogen-bonded water molecules make critical contributions to the assembly and stability of the trimer-of-hairpins form of the BLV TM and are essential for TM-mediated fusion. Additionally, we resolve a region of the LHR that is critical to the activity of peptide inhibitors of HTLV-1 and BLV entry. We provide evidence that basic residues in a membrane proximal helical element of the LHR interact with charged residues that surround an extended hydrophobic pocket on the coiled coil. This charge-surrounded pocket represents an attractive target for antiviral drugs. Our data indicate that coordinated ions and charge-surrounded hydrophobic pockets are functionally significant leitmotifs of class I fusion proteins.