冷激活瞬时受体电位通道 TRPM8 对冷却剂和脂质的感应结构基础。
Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel.
机构信息
Department of Biochemistry, Duke University School of Medicine, Durham, NC, 27710, USA.
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
出版信息
Science. 2019 Mar 1;363(6430). doi: 10.1126/science.aav9334. Epub 2019 Feb 7.
Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca)-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP, and Ca, as well as in complex with the menthol analog WS-12 and PIP Our structures reveal the binding sites for cooling agonists and PIP in TRPM8. Notably, PIP binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.
瞬时受体电位 melastatin 成员 8（TRPM8）是一种钙离子（Ca）通透阳离子通道，是人类中主要的冷和薄荷醇感受器。冷却化合物通过变构作用激活 TRPM8，依赖于激动剂和膜脂磷脂酰肌醇 4,5-二磷酸（PIP）的作用，但缺乏结构信息，迄今为止，TRPM8 对配体和脂质的感应机制仍不清楚。本研究利用冷冻电子显微镜技术，测定了 TRPM8 与合成冷却化合物 icilin、PIP 和 Ca 复合物的结构，以及与薄荷醇类似物 WS-12 和 PIP 复合物的结构。我们的结构揭示了 TRPM8 中冷却激动剂和 PIP 的结合位点。值得注意的是，PIP 以两种不同的模式结合 TRPM8，说明了 PIP 和激动剂之间变构偶联的机制。这项研究为理解冷却剂激活 TRPM8 的分子机制提供了一个平台。
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