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Elucidating the molecular details of pentameric Ligand Gated Ion Channels: lipid interactions, gating, and membrane models

Dr. Pramod Kumar, University of Illinois, Urbana-Champaign, USA

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Abstract:
Ion channels are membrane proteins that allow the flow of ions into and out of the cell. This flow of ions creates an electrical signal that forms the basis of physiological processes such as neurotransmission and muscular contraction. To regulate the flow of ions, ion channels have evolved to be responsive to a large number of stimuli such as voltage, osmotic pressure, and the binding of small molecules. One of the most extensively studied superfamilies of ion channels is that of the pentameric ligand gated ion channels (pLGIC), which shares an overall topology whereby five protein subunits come together in the membrane to form a pore which gates the ions and encompassing members either function as excitatory by regulating cations or inhibitory by regulating anions. It has been known for decades that functioning of the channel directly influenced by surrounding lipids—as evident from simple ligand binding assays where poor agonists affinity has been observed for micelles stabilized form vs almost native-like affinity for lipid stabilized channels—the lack of sufficient structure-function studies in native and engineered lipid environment hampered the understanding of lipid dependence of agonism and ion channel gating. This presentation describes my original work on the fundamental understanding of the mechanistic details of coupling between ligand binding and gating, lipid dependence and effect of targeted mutations, agonism, and restoration of function by customized lipid profiling—directly elucidate the structural-functional basis of agonism and lipid dependence and has straight forward application in the development of membrane mimetics with potential use in customized drug development against neurological disorders. Furthermore, the high-resolution Cryo-EM structures of model pLGIC in synthetic and native lipids along with electrophysiological studies present the cutting age application of modern biophysical techniques to explore the structure-function underpinning in pLGIC family in particular and the nature of allosterism in general.

Meeting ID: 938 5139 7707
Passcode: 735416
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