• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>PLoS Biology >The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ
【2h】

The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ

机译：人核激素受体REV-ERBβ的气体响应转录的结构基础

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Heme is a ligand for the human nuclear receptors (NR) REV-ERBα and REV-ERBβ, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV-ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ligand-binding domain (LBD). A 1.9 Å crystal structure of the REV-ERBβ LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-binding pocket, where the heme iron is coordinately bound by histidine 568 and cysteine 384. Under reducing conditions, spectroscopic studies of the heme-REV-ERBβ complex reveal that the Fe(II) form of the LBD transitions between penta-coordinated and hexa-coordinated structural states, neither of which possess the Cys384 bond observed in the oxidized state. In addition, the Fe(II) LBD is also able to bind either NO or CO, revealing a total of at least six structural states of the protein. The binding of known co-repressors is shown to be highly dependent upon these various liganded states. REV-ERBs are thus highly dynamic receptors that are responsive not only to heme, but also to redox and gas. Taken together, these findings suggest new mechanisms for the systemic coordination of molecular clocks and metabolism. They also raise the possibility for gas-based therapies for the many disorders associated with REV-ERB biological functions.
机译：血红素是人类核受体（NR）REV-ERBα和REV-ERBβ的配体，它们在昼夜节律，脂质和葡萄糖代谢以及诸如糖尿病，动脉粥样硬化，炎症和癌症等疾病中起重要作用。在这里我们表明，通过添加一氧化氮（NO）可以逆转由血红素结合的REV-ERBs介导的转录抑制，并且血红素和NO的作用是由C端配体结合域（LBD）介导的。 REV-ERBβLBD的1.9Å晶体结构与氧化的血红素Fe（III）形成复合物，表明血红素结合在典型的NR配体结合口袋中，其中血红素铁被组氨酸568和半胱氨酸协调结合384.在还原条件下，对血红素-REV-ERBβ配合物的光谱研究表明，LBD的Fe（II）形式在五配位和六配位结构态之间转变，在氧化态下均不具有Cys384键州。另外，Fe（II）LBD还能够结合NO或CO，从而揭示出该蛋白质的至少六个结构状态。已知的共阻抑物的结合显示出高度依赖于这些各种配体状态。因此，REV-ERB是高度动态的受体，不仅对血红素有反应，而且对氧化还原和气体也有反应。综上所述，这些发现为分子钟和新陈代谢的系统协调提供了新的机制。它们还增加了针对与REV-ERB生物学功能相关的多种疾病进行基于气体疗法的可能性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

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