The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta.
The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBbeta.
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DOI：
10.1371/journal.pbio.1000043
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发表时间：
2009-02-24
期刊：
影响因子：
9.8
通讯作者：
Edwards A
中科院分区：
文献类型：
--
作者：
Pardee KI;Xu X;Reinking J;Schuetz A;Dong A;Liu S;Zhang R;Tiefenbach J;Lajoie G;Plotnikov AN;Botchkarev A;Krause HM;Edwards A
血红素是人核受体（NR）REV-ERBα和REV-ERBβ的配体，其是在昼夜节律、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发挥重要作用的转录抑制因子。在这里，我们表明，血红素结合REV-ERBs介导的转录抑制被逆转的一氧化氮（NO）的加入，血红素和NO的影响是由C-末端配体结合域（LBD）介导的。REV-ERBβ LBD的1.9 nm晶体结构与血红素的氧化Fe（III）形式复合，表明血红素结合在原型NR配体结合口袋中，其中血红素铁与组氨酸568和半胱氨酸384配位结合。在还原条件下，血红素-REV-ERBβ复合物的光谱研究表明，Fe（II）形式的LBD在五配位和六配位结构状态之间转换，这两种结构状态都不具有在氧化态中观察到的Cys 384键。此外，Fe（II）LBD还能够结合NO或CO，揭示了蛋白质的至少六种结构状态。已知的辅阻遏物的结合显示出高度依赖于这些不同的配体状态。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。总之，这些发现表明了分子钟和代谢系统协调的新机制。他们还提出了基于气体的治疗与REV-ERB生物功能相关的许多疾病的可能性。许多人类生物学，如睡眠，饮食，甚至心脏病发作的患病率，都发生在日常周期中。这些周期是由位于大脑中的主“时钟”协调的。这个生物钟的基本组成部分是控制重要基因表达的蛋白质。在这项研究中，我们分析了这些调节蛋白之一，命名为REV-ERB，并表明它是由血红素和一氧化氮气体，这两者都是人体生理学的重要调节剂的组合调节。通过确定REV-ERB蛋白的三维结构，我们能够揭示这种调节如何发生的线索。REV-ERB属于一个称为核激素受体的蛋白质家族，已知它们是极好的药物靶点。因此，这篇论文为已知涉及REV-ERB的疾病（如糖尿病、动脉粥样硬化、炎症和癌症）的可能的气体疗法打开了大门。血红素调节的核激素受体REV-ERB是调节昼夜节律的核心转录因子之一。我们发现血红素结合REV-ERB的转录受NO气体的调节，血红素结合蛋白的晶体结构揭示了血红素和气体结合的基础。
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. Much of human biology, such as sleeping, eating, and even the prevalence of heart attacks, occurs in daily cycles. These cycles are orchestrated by a master “clock” located in the brain. The basic components of this clock are proteins that control the expression of important genes. In this study, we analyze one of these regulatory proteins, named REV-ERB, and show that it is regulated by the combination of heme and nitric oxide gas, both of which are important regulators of human physiology. By determining the 3-D structure of the REV-ERB protein, we were able to uncover clues as to how this regulation occurs. REV-ERB belongs to a protein family called nuclear hormone receptors, which are known to be excellent drug targets. Thus, this paper opens the door to possible gas-based therapies for diseases known to involve REV-ERB, such as diabetes, atherosclerosis, inflammation, and cancer. The heme-regulated nuclear hormone receptor REV-ERB is one of the core transcription factors regulating circadian rhythms. We found that transcription by heme-bound REV-ERB is regulated by NO gas, and a crystal structure of the heme-bound protein uncovers the basis for heme and gas binding.
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影响因子：
4.8
作者：
Coste, H;Rodríguez, JC
通讯作者：
Rodríguez, JC
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
14.9
作者：
Burke, L;Downes, M;Muscat, GEO
通讯作者：
Muscat, GEO
影响因子：
2.9
作者：
de Rosny, Eve;de Groot, Arjan;Jouve, Helene M.
通讯作者：
Jouve, Helene M.
影响因子：
14.9
作者：
Downes, M;Burke, LJ;Muscat, GEO
通讯作者：
Muscat, GEO