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Tight junction (TJ) barriers between the brain and body are disrupted in many diseases and are key to neuro-active drug design, yet remain poorly understood. This project addresses that gap by employing oligomeric nanodisc assemblies to solve high-resolution structures of key TJ barrier proteins, Claudins 1, 2, 3, 5, and 11, and Occludin, thus laying the groundwork for rational development of improved neurotherapeutics.