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Druggable Lipid Binding Sites in Pentame Ligand-Gated Ion Channels and Transient Receptor Potential Channels

Cheng WWL, Arcario MJ, Petroff JT

Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. In their research, the authors review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels and discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites.