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Trimeric class I virus fusion proteins undergo a series of conformational rearrangements that leads to the association of C- and N-terminal heptad repeat domains in a “trimer-of-hairpins” structure, facilitating the apposition of viral and cellular membranes during fusion. This final fusion hairpin structure is sustained by protein–protein interactions, associations thought initially to be refractory to small-molecule inhibition because of the large surface area involved. By using a photoaffinity analog of a potent respiratory syncytial virus fusion inhibitor, we directly probed the interaction of the inhibitor with its fusion protein target. Studies have shown that these inhibitors bind within a hydrophobic cavity formed on the surface of the N-terminal heptad-repeat trimer. In the fusogenic state, this pocket is occupied by key amino acid residues from the C-terminal heptad repeat that stabilize the trimer-of-hairpins structure. The results …