...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Membrane-tethered ligands are effective probes for exploring class B1 G protein-coupled receptor function
【24h】

Membrane-tethered ligands are effective probes for exploring class B1 G protein-coupled receptor function

机译：膜连接的配体是探索B1 G类蛋白偶联受体功能的有效探针

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

Class B1 (secretin family) G protein-coupled receptors (GPCRs) modulate a wide range of physiological functions, including glucose homeostasis, feeding behavior, fat deposition, bone remodeling, and vascular contractility. Endogenous peptide ligands for these GPCRs are of intermediate length (27-44 aa) and include receptor affinity (C-terminal) as well as receptor activation (N-terminal) domains. We have developed a technology in which a peptide ligand tethered to the cell membrane selectively modulates corresponding class B1 GPCR-mediated signaling. The engineered cDNA constructs encode a single protein composed of (i) a transmembrane domain (TMD) with an intracellular C terminus, (ii) a poly(asparagine-glycine) linker extending from the TMD into the extracellular space, and (iii) a class B1 receptor ligand positioned at the N terminus. We demonstrate that membrane-tethered pep-tides, like corresponding soluble ligands, trigger dose-dependent receptor activation. The broad applicability of this approach is illustrated by experiments using tethered versions of 7 mammalian endogenous class B1 GPCR agonists. In parallel, we carried out mutational studies focused primarily on incretin ligands of the glucagon-like peptide-1 receptor. These experiments suggest that tethered ligand activity is conferred in large part by the N-terminal domain of the peptide hormone. Follow-up studies revealed that interconversion of tethered agonists and antagonists can be achieved with the introduction of selected point mutations. Such complementary receptor modulators provide important new tools for probing receptor structure-function relationships as well as for future studies aimed at dissecting the tissue-specific biological role of a GPCR in vivo (e.g., in the brain vs. in the periphery).
机译：B1类（分泌蛋白家族）G蛋白偶联受体（GPCR）调节多种生理功能，包括葡萄糖稳态，进食行为，脂肪沉积，骨骼重塑和血管收缩。这些GPCR的内源肽配体具有中等长度（27-44aa），并且包括受体亲和力（C端）和受体激活（N端）域。我们已经开发出一种技术，其中拴在细胞膜上的肽配体选择性地调节相应的B1类GPCR介导的信号传导。工程化的cDNA构建体编码单个蛋白质，该蛋白质由（i）具有细胞内C末端的跨膜结构域（TMD），（ii）从TMD延伸到细胞外空间的聚（天冬酰胺-甘氨酸）接头和（iii） B1类受体配体位于N末端。我们证明，像相应的可溶性配体一样，膜拴肽段会触发剂量依赖性受体激活。该方法的广泛适用性通过使用7种哺乳动物内源性B1类GPCR激动剂的束缚版本进行的实验说明。同时，我们进行了主要针对胰高血糖素样肽1受体的肠降血糖素配体的突变研究。这些实验表明，拴系的配体活性很大程度上是由肽激素的N末端结构域赋予的。后续研究表明，可以通过引入选定的点突变来实现拴系激动剂和拮抗剂的相互转化。这样的互补受体调节剂提供了重要的新工具，用于探索受体结构-功能关系以及用于将来在体内解剖GPCR的组织特异性生物学作用的研究（例如，在脑中对在外周中）。

著录项

  • 来源
  • 作者

    Jean-Philippe Fortin; Yuantee Zhu; Charles Choi; Martin Beinborn; Michael N. Nitabach; Alan S. Kopin;

  • 作者单位

    Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111;

    Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111;

    Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520;

    Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111;

    Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520;

    Molecular Pharmacology Research Center, Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111;

  • 收录信息 美国《科学引文索引》(SCI);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

    agonist; antagonist; GPCR; incretins; peptide hormones;

    机译：激动剂拮抗剂GPCR;肠降血糖素肽激素;

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