A Global Map of Lipid-Binding Proteins and Their Ligandability in Cells.
A Global Map of Lipid-Binding Proteins and Their Ligandability in Cells.
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DOI：
10.1016/j.cell.2015.05.045
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发表时间：
2015-06-18
期刊：
影响因子：
64.5
通讯作者：
Cravatt BF
中科院分区：
文献类型：
--
作者：
Niphakis MJ;Lum KM;Cognetta AB 3rd;Correia BE;Ichu TA;Olucha J;Brown SJ;Kundu S;Piscitelli F;Rosen H;Cravatt BF
脂质在生理和疾病中发挥着核心作用，其结构、代谢和信号功能通常来自与蛋白质的相互作用。在这里，我们描述了一组基于脂质的化学蛋白质组学探针及其在哺乳动物细胞中的全局相互作用图。这些相互作用涉及来自不同功能类别的数百种蛋白质，并且经常发生在药物作用部位。我们确定了几种药物在脂质相互作用蛋白质组中的靶谱，揭示了其配体含量远远超出了传统定义的可药物蛋白质类别。为了进一步支持这一发现，我们描述了一种脂质结合蛋白核结合蛋白-1 （NUCB1）的选择性配体，并表明该化合物干扰细胞内源性大麻素的水解和氧化代谢。因此，所描述的化学蛋白质组学平台提供了一种发现和药理学表征细胞中参与脂质途径的广泛蛋白质的综合途径。
Lipids play central roles in physiology and disease, where their structural, metabolic, and signaling functions often arise from interactions with proteins. Here, we describe a set of lipid-based chemical proteomic probes and their global interaction map in mammalian cells. These interactions involve hundreds of proteins from diverse functional classes and frequently occur at sites of drug action. We determine the target profiles for several drugs across the lipidinteraction proteome, revealing that its ligandable content extends far beyond traditionally defined categories of druggable proteins. In further support of this finding, we describe a selective ligand for the lipid-binding protein nucleobindin-1 (NUCB1) and show that this compound perturbs the hydrolytic and oxidative metabolism of endocannabinoids in cells. The described chemical proteomic platform thus provides an integrated path to both discover and pharmacologically characterize a wide range of proteins that participate in lipid pathways in cells.