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

Autor:	Cheng WWL; Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States., Arcario MJ; Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States., Petroff JT 2nd; Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2022 Jan 04; Vol. 12, pp. 798102. Date of Electronic Publication: 2022 Jan 04 (Print Publication: 2021).
DOI:	10.3389/fphys.2021.798102
Abstrakt:	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. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We 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. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Cheng, Arcario and Petroff.)
Databáze:	MEDLINE
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