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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The conformation of neurotensin bound to its G protein-coupled receptor
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The conformation of neurotensin bound to its G protein-coupled receptor

机译：神经降压素与其G蛋白偶联受体结合的构象

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摘要

G protein-coupled receptors (GPCRs) mediate the perception of smell, light, taste, and pain. They are involved in signal recognition and cell communication and are some of the most important targets for drug development. Because currently no direct structural information on high-affinity ligands bound to GPCRs is available, rational drug design is limited to computational prediction combined with mutagenesis experiments. Here, we present the conformation of a high-affinity peptide agonist (neurotensin, NT) bound to its GPCR NTS-1, determined by direct structural methods. Functional receptors were expressed in Escherichia coli, purified in milligram amounts by using optimized procedures, and subsequently reconstituted into lipid vesicles. Solid-state NMR experiments were tailored to allow for the unequivocal detection of microgram quantities of C-13,N-15-labeled NT(8-13) in complex with functional NTS-1. The NMR data are consistent with a disordered state of the ligand in the absence of receptor. Upon receptor binding, the peptide undergoes a linear rearrangement, adopting a beta-strand conformation. Our results provide a viable structural template for further pharmacological investigations. [References: 57]
机译：G蛋白偶联受体（GPCR）介导嗅觉，光线，味道和疼痛感。它们参与信号识别和细胞通讯，并且是药物开发的一些最重要的目标。由于目前尚无有关与GPCR结合的高亲和力配体的直接结构信息，因此合理的药物设计仅限于结合诱变实验的计算预测。在这里，我们介绍通过直接结构方法确定的与其GPCR NTS-1结合的高亲和力肽激动剂（神经降压素，NT）的构象。功能受体在大肠杆菌中表达，通过使用优化程序以毫克量纯化，然后重构为脂质囊泡。进行了固态NMR实验，以明确检测具有功能性NTS-1的复合物中微克数量的C-13，N-15标记的NT（8-13）。 NMR数据与不存在受体时配体的无序状态一致。在受体结合后，该肽进行线性重排，采用β链构象。我们的结果为进一步的药理研究提供了可行的结构模板。 [参考：57]

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