Cryo-EM reveals mechanisms of gating and drug modulation in 5-HT3A receptors
Over the last 20 years, Dr. Sudha Chakrapani's research 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. This talk will focus on the serotonin (3A) receptor (5HT3AR), a member of the pLGIC family, regulating gut functions such as motility, secretion, and visceral perception. Using single-particle cryo-electron microscopy, her team solved structures of the full-length 5HT3AR in the resting state, in serotonin-activated conformations, and in complex with several clinically used drugs called setron. Setrons are widely used in the treatment of nausea and vomiting in patients undergoing cancer treatments and in the management of visceral pain in conditions such as irritable bowel syndrome. Taken together, their structural findings revealed detailed insights into mechanisms underlying 5HT3AR activation and drug modulation. These structures serve as molecular blueprints for the design of novel therapeutic agents targeting 5-HT3AR.
Director, Cleveland Center for Membrane and Structural Biology