• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Smoothened stimulation by membrane sterols drives Hedgehog pathway activity
【24h】

Smoothened stimulation by membrane sterols drives Hedgehog pathway activity

机译：通过膜甾醇促进刺激驱动刺猬途径活动

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

Hedgehog signalling is fundamental to embryonic development and postnatal tissue regeneration(1). Aberrant postnatal Hedgehog signalling leads to several malignancies, including basal cell carcinoma and paediatric medulloblastoma(2). Hedgehog proteins bind to and inhibit the transmembrane cholesterol transporter Patched-1 (PTCH1), which permits activation of the seven-transmembrane transducer Smoothened (SMO) via a mechanism that is poorly understood. Here we report the crystal structure of active mouse SMO bound to both the agonist SAG21k and to an intracellular binding nanobody that stabilizes a physiologically relevant active state. Analogous to other G protein-coupled receptors, the activation of SMO is associated with subtle motions in the extracellular domain, and larger intracellular changes. In contrast to recent models(3-5), a cholesterol molecule that is critical for SMO activation is bound deep within the seven-transmembrane pocket. We propose that the inactivation of PTCH1 by Hedgehog allows a transmembrane sterol to access this seven-transmembrane site (potentially through a hydrophobic tunnel), which drives the activation of SMO. These results-combined with signalling studies and molecular dynamics simulations-delineate the structural basis for PTCH1-SMO regulation, and suggest a strategy for overcoming clinical resistance to SMO inhibitors.
机译：刺猬信号是胚胎发育和产后组织再生的基础（1）。异常的后期刺猬信号导致几种恶性肿瘤，包括基础细胞癌和儿科髓质母细胞瘤（2）。刺猬蛋白质结合并抑制跨膜胆固醇转运蛋白贴剂-1（PTCH1），其允许通过较差地理解的机制使七跨膜换能器变平滑（SMO）。在这里，我们报告了与激动剂SAG21K的活性小鼠SMO的晶体结构和稳定生理学相关的活性状态的细胞内结合纳米体。类似于其他G蛋白偶联受体，SMO的活化与细胞外结构域中的微妙动作相关，细胞内变化较大。与最近的模型（3-5）相反，对于Smo活化至关重要的胆固醇分子是末端的七跨膜袋中的深层。我们建议刺猬灭活PTCH1允许跨膜甾醇进入该七跨膜部位（可能通过疏水隧道），这驱动了Smo的激活。这些结果与信号研究和分子动力学模拟相结合 - 描绘了PTCH1-SMO调节的结构基础，并提出了一种克服临床抗性抑制剂的策略。

著录项

  • 来源
    《Nature》 |2019年第7764期|284-288|共5页
  • 作者

    Deshpande Ishan; Liang Jiahao; Hedeen Danielle; Roberts Kelsey J.; Zhang Yunxiao; Ha Betty; Latorraca Naomi R.; Faust Bryan; Dror Ron O.; Beachy Philip A.; Myers Benjamin R.; Manglik Aashish;

  • 作者单位

    Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA;

    Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA;

    Univ Utah Sch Med Dept Oncol Sci Salt Lake City UT USA|Univ Utah Sch Med Huntsman Canc Inst Salt Lake City UT USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Stanford Univ Sch Med Dept Dev Biol Stanford CA 94305 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA;

    Stanford Univ Sch Med Dept Mol & Cellular Physiol Stanford CA 94305 USA|Stanford Univ Sch Med Dept Struct Biol Stanford CA 94305 USA|Stanford Univ Dept Comp Sci Stanford CA 94305 USA|Stanford Univ Inst Computat & Math Engn Stanford CA 94305 USA;

    Stanford Univ Sch Med Dept Mol & Cellular Physiol Stanford CA 94305 USA|Stanford Univ Sch Med Dept Struct Biol Stanford CA 94305 USA|Stanford Univ Dept Comp Sci Stanford CA 94305 USA|Stanford Univ Inst Computat & Math Engn Stanford CA 94305 USA|Stanford Univ Biophys Program Stanford CA 94305 USA;

    Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA;

    Stanford Univ Sch Med Dept Mol & Cellular Physiol Stanford CA 94305 USA|Stanford Univ Sch Med Dept Struct Biol Stanford CA 94305 USA|Stanford Univ Dept Comp Sci Stanford CA 94305 USA|Stanford Univ Inst Computat & Math Engn Stanford CA 94305 USA|Stanford Univ Biophys Program Stanford CA 94305 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Stanford Univ Sch Med Dept Dev Biol Stanford CA 94305 USA|Stanford Univ Sch Med Dept Urol Stanford CA 94305 USA|Stanford Univ Sch Med Chem & Syst Biol Stanford CA 94305 USA;

    Stanford Univ Sch Med Inst Stem Cell Biol & Regenerat Med Stanford CA 94305 USA|Univ Utah Sch Med Dept Oncol Sci Salt Lake City UT 84112 USA|Univ Utah Sch Med Huntsman Canc Inst Salt Lake City UT 84112 USA;

    Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA|Univ Calif San Francisco Dept Anesthesia & Perioperat Care San Francisco CA 94143 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