Abstract

Small-molecule modulators, including drinking alcohol, are known to bind intersubunit transmembrane sites in pentameric ligand-gated ion channels. However, due in part to the controversial functional annotations of published structures, the molecular basis and mechanistic impact of these interactions remain unclear. Using the bacterial model protein GLIC, we applied a combination of oocyte electrophysiology, structural biology, and molecular dynamics simulations to characterize alcohol interactions associated with particular functional states. Mutations at the subunit interface stabilized solvent-mediated interfacial contacts specific to the apparent open state, a mechanism distinct from mutations in the channel pore, leading to nonadditive effects on gating. We also found evidence for both potentiation and inhibition via distinct allosteric sites, depending on the functional state most favorably bound. Our results provide structural and dynamic detail for an allosteric model of ion channel gating and modulation, including a critical role for solvation at subunit interfaces.

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