Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels.
Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels.
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DOI：
10.3389/fphys.2021.798102
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发表时间：
2021
影响因子：
4
通讯作者：
Petroff JT 2nd
中科院分区：
文献类型：
--
作者：
Cheng WWL;Arcario MJ;Petroff JT 2nd
脂质调节许多离子通道的功能，可能是通过脂质与蛋白质的直接相互作用。最近通过低温电镜观察到的离子通道结构揭示了许多脂质结合位点。在大多数情况下，这些位点是否介导离子通道功能的脂质调节尚不明确。然而，有趣的是，许多这些脂质结合位点也是其他变构调节剂或药物的已知位点，这支持了脂质通过这些位点作为内源性变构调节剂的概念。在这里，我们回顾了这些脂质药物结合位点，重点是五聚体配体门控离子通道和瞬时受体电位通道。值得注意的例子包括由麻醉药和香草类药物共享的磷脂和固醇的位点。我们讨论了脂质结合在这些位点的一些含义，包括脂质可以改变药物效力的可能性，或者理解蛋白质-脂质相互作用可以指导药物设计。结构只是了解这些部位脂质调节机制的第一步。展望未来，我们确定了该领域的知识差距，并提出了解决这些差距的方法。这些包括使用不对称膜定义脂质对重构系统中通道功能的影响，以及使用天然质谱法、荧光结合测定和计算方法测量特定位点的脂质结合亲和力。
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.
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3.4
作者：
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