美国加州大学圣地亚哥分校确定了一种完整的未经修饰的G蛋白偶联受体,即CXCR1,在自然环境-在生理学条件下嵌入磷脂双层膜-中的三维结构。

-2012年11月29日《自然》

中文翻译


【题目】磷脂双层中趋化因子受体CXCR1的结构

【译文】CXCR1是CXC趋化因子白介素8(IL-8)两种高亲和受体之一,它是许多疾病(包括肿瘤生长)相关的免疫和炎症反应的主要调控因子。IL-8由炎症刺激诱导产生,能与胞外侧的CXCR1结合。配体激活的胞内信号通路导致中性粒细胞迁移至炎症位点。CXCR1是一类A型视紫红质样G蛋白偶联受体(GPCR),这是负责细胞信号转导和药物受体靶向的最大家族的膜内在蛋白。虽然其很重要,但CXCR1信号转导的分子机制尚不清楚,这主要是因为有限可用的结构信息。近期GPCRs的结构确定已经通过修饰具有稳定突变的受体,蛋白T4溶菌酶的插入,这些氨基酸序列的截短,以及在三相位甘油单油酸酯混合物中添加稳定抗体和有利于结晶的小分子,而取得了进展。GPCRs的胞内杂环对于G蛋白相互作用至关重要,而CXCR1的活化涉及到氨基末端残基和胞外杂环。我们先前的核磁共振研究表明与N末端残基结合的IL-8是由膜介导的,突出了磷脂双层对生理活性的重要性。本研究利用NMR光谱法解析了人CXCR1的三维结构。在生理条件下,该受体位于液相结晶的磷脂双层中,其氨基酸序列没有修饰。对于胞内G蛋白活化和信号转导重要的特征也被揭示。脂双层中人CXCR1的结构可能有助于对与GPCRs相互作用以及对抗疾病(如乳腺癌)的新复合物的发现。

关键词: 趋化因子受体CXCR1,磷脂双分子层,结构

Key words: chemokine-receptor-CXCR1-phospholipid-bilayers-structure, nature,nature-2012-11-29

英文原稿[Title]: Structure of the chemokine receptor CXCR1 in phospholipid bilayers

[Authors]:Sang Ho Park,1 Bibhuti B. Das,1 Fabio Casagrande,1 Ye Tian,1, 2 Henry J. Nothnagel,1 Mignon Chu,1 Hans Kiefer,3 Klaus Maier,4 Anna A. De Angelis,4 Francesca M. Marassi2 & Stanley J. Opella1  

[Abstract]CXCR1 is one of two high-affinity receptors for the CXC chemokine interleukin-8 (IL-8), a major mediator of immune and inflammatory responses implicated in many disorders, including tumour growth. IL-8, released in response to inflammatory stimuli, binds to the extracellular side of CXCR1. The ligand-activated intracellular signalling pathways result in neutrophil migration to the site of inflammation. CXCR1 is a class A, rhodopsin-like G-protein-coupled receptor (GPCR), the largest class of integral membrane proteins responsible for cellular signal transduction and targeted as drug receptors. Despite its importance, the molecular mechanism of CXCR1 signal transduction is poorly understood owing to the limited structural information available. Recent structural determination of GPCRs has advanced by modifying the receptors with stabilizing mutations, insertion of the protein T4 lysozyme and truncations of their amino acid sequences, as well as addition of stabilizing antibodies and small molecules that facilitate crystallization in cubic phase monoolein mixtures. The intracellular loops of GPCRs are crucial for G-protein interactions, and activation of CXCR1 involves both amino-terminal residues and extracellular loops. Our previous nuclear magnetic resonance studies indicate that IL-8 binding to the N-terminal residues is mediated by the membrane, underscoring the importance of the phospholipid bilayer for physiological activity. Here we report the three-dimensional structure of human CXCR1 determined by NMR spectroscopy. The receptor is in liquid crystalline phospholipid bilayers, without modification of its amino acid sequence and under physiological conditions. Features important for intracellular G-protein activation and signal transduction are revealed. The structure of human CXCR1 in a lipid bilayer should help to facilitate the discovery of new compounds that interact with GPCRs and combat diseases such as breast cancer.

原文地址http://www.nature.com/nature/journal/v491/n7426/full/nature11580.html

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