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Nature:结构分析µ-阿片受体激发原因

摘要 : µ-阿片受体是被各种止痛药、内源性内啡肽和被滥用的药物如海洛因和鸦片激发的一种“G-蛋白耦合受体”。

 µ-阿片受体是被各种止痛药、内源性内啡肽和被滥用的药物如海洛因和鸦片激发的一种“G-蛋白耦合受体”。我们对激动剂的结合导致某一特定的G-蛋白子类被识别、耦合和激发的机制还不完全了解。在本期Nature上的两篇论文中,作者采用X-射线晶体学方法、分子动态模拟方法和NMR光谱方法对受体激发的结构基础进行了研究。除了揭示这一GPCR在细胞外和细胞内区域中所发生的与受体激发相关的构形变化外,这两项研究也可帮助解释为什么这一受体的激动剂结合穴与胞质G-蛋白耦合界面之间的变构耦合相对较弱。

原文链接:

Structural insights into µ-opioid receptor activation

原文摘要:

Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β2-adrenergic receptor (β2AR) and the M2 muscarinic receptor. Comparison with active β2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.

来源: Nature 浏览次数:0

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