• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor
【24h】

Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor

机译：G蛋白偶联受体胞外表面的配体特异性调节

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the β_2 adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures.
机译：G蛋白偶联受体（GPCR）是七种跨膜蛋白，可介导大多数细胞对激素和神经递质的反应。它们是广泛疾病的最大治疗靶标。 GPCR的最新晶体结构已揭示出结构保守性，其范围从跨膜核心中的正构配体结合位点延伸至胞质G蛋白偶联结构域。相反，GPCR的细胞外表面（ECS）非常多样，因此是发现亚型选择性药物的理想靶标。然而，关于ECS在受体激活中的功能作用，或该表面与天然配体结合口袋的构象偶联，知之甚少。在这里，我们使用NMR光谱技术来研究围绕β_2肾上腺素能受体ECS中心结构特征的配体特异性构象变化：连接细胞外环2和3的盐桥。小分子药物在跨膜核心内结合并表现出不同的功效对G蛋白激活（激动剂，中性拮抗剂和反向激动剂）的作用还可以稳定ECS的独特构象。因此，我们证明了ECS与正构结合位点之间的构象偶联，表明靶向这种不同表面的药物可以作为具有高亚型选择性的变构调节剂。此外，这些研究为无法通过静态，非活动状态晶体结构解决的GPCR的动态行为提供了新的见识。

著录项

  • 来源
    《Nature》 |2010年第7277期|108-112|共5页
  • 作者

    Michael P. Bokoch; Yaozhong Zou; Soren G. F. Rasmussen; Corey W. Liu; Rie Nygaard; Daniel M. Rosenbaum; Juan Jose Fung; Hee-Jung Choi; Foon Sun Thian; Tong Sun Kobilka; Joseph D. Puglisi; William I. Weis; Leonardo Pardo; R. Scott Prosser; Luciano Mueller; Brian K. Kobilka;

  • 作者单位

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Stanford Magnetic Resonance Laboratory, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Stanford Magnetic Resonance Laboratory, Stanford University School of Medicine, Stanford, California 94305, USA Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA;

    Laboratori de Medicina Computacional, Unitat de Bioestadistica, Universitat Autonoma de Barcelona, 08193 Bellaterra (Barcelona), Spain;

    Department of Chemistry, University of Toronto, UTM, Mississauga, Ontario, Canada L5L 1C6;

    Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA;

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号