University of Cambridge > Talks.cam > Biophysical Seminars > Gating Mechanisms and drug modulation in Pentameric Ligand-gated Ion Channels: Insights from Cryo-EM

Gating Mechanisms and drug modulation in Pentameric Ligand-gated Ion Channels: Insights from Cryo-EM

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If you have a question about this talk, please contact Akhila Kadgathur Jayaram.

My research over the last 20 years has focused on ion channels that mediate fast synaptic transmission at the neuronal and neuromuscular junctions. Among these channel classes, the pentameric ligand-gated ion channel (pLGIC) superfamily governs crucial physiological processes such as gastrointestinal functions, motor functions, and pain transmission. Aberrant channel functions are implicated in neurological disorders, mood disorders, addiction, and chronic pain. Currently used therapeutic strategies suffer from our limited knowledge of the molecular details of pLGIC function, the origin of their functional diversity, and the downstream signaling events. Using single-particle cryo-electron microscopy, we solved structures of the full-length serotonin receptor (5HT3AR), a cationic pLGIC, in the resting state and two serotonin-activated conformations. More recently, we have solved the structures of full-length glycine receptor (GlyR), in a membrane environment, in the resting, open, and desensitized states. Building on these advancements, we have now determined high-resolution snap-shots of drug-bound conformations of both 5HT3AR and GlyRs. Taken together, these findings provide molecular blueprints of the channel in physiologically relevant conformations for therapeutic targeting and pave the way for design of novel therapeutic agents that are safer and more effective.

This talk is part of the Biophysical Seminars series.

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