The integral membrane protein p7 from hepatitis C virus (HCV) can self-assemble into a large cation channel, or viroporin, which is required for viral replication and is a potential anti-HCV drug target. Chou and colleagues have now determined the NMR structure of the large hexameric p7 channel reconstituted in micelles. Each monomer consists of three helices (H1–H3), and the monomers intertwine to form a tightly packed channel, with H1 and H2 forming the channel interior. Each monomer interacts not only with its direct neighboring monomers but also with the +2 and +3 monomers, thereby forming an unusual funnel-like structure. To define the elements involved in cation conductance and gating, the authors identified highly conserved polar residues in the channel interior. Asn9 (His9 in some strains) has affinity for monovalent and divalent cations, and forms a ring that was proposed to serve as a broad selectivity filter at the narrow end of the funnel. Replacement of His9 with alanine caused a large reduction in channel conductance. The Ile6 ring at the funnel's narrowest point forms a hydrophobic gate that is thought to prevent water passage. Arg35 forms a positively charged ring at the wider, C-terminal end of the channel and was proposed to bind and obstruct anions at the pore entrance while allowing unidirectional cation diffusion. As expected, mutation of Arg35 to a negatively charged residue hindered the diffusion of cations into the pore and reduced conductance. The available NMR data suggest that adamantine-derived drugs bind six equivalent hydrophobic pockets between the pore-forming and peripheral helices. As channel activation may involve structural rearrangements, the binding of adamantine derivatives might allosterically inhibit cation conduction by restricting movements of the three helical segments, thereby preventing the channel from opening. More rigorous testing will be required to validate this attractive model. (Nature 498, 521–525, 2013)