核受体LRH-1通过使用不同的全信号电路来区分连接体
Suzanne G Mays1,2, David Hercules1, Eric A Ortlund1
1Department of Biochemistry, Emory University, Atlanta, Georgia, USA.
Protein science : a publication of the Protein Society
|August 12, 2023
概括
使用分子动力学研究了肝受体同源-1 (LRH-1) 的全信号传递. 鉴定了活跃和非活跃带到激活函数表面的不同通信途径,揭示了新的治疗点.
科学领域:
- 分子生物学分子生物学
- 结构生物学 结构生物学
- 生物化学 生化学
背景情况:
- 核受体 (NR) 是对连接体有反应的转录因子,控制着重要的生物过程.
- NR功能依赖于连接体诱导的构造变化,将信号从连接体结合口袋传输到激活功能表面 (AFS).
- 这种全osteric 通信的精确机制仍然不完全理解.
研究的目的:
- 阐明控制肝受体同类-1 (LRH-1) 激活的全性通信网络.
- 了解不同的连接体如何调解与AFS的通信,以获得不同的转录结果.
- 探索LRH-1在发育,新陈代谢,癌症和炎症中的作用.
主要方法:
- 对74个不同的LRH-1复合体进行了广泛的全原子分子动力学模拟 (>100μs).
- 信号电路和全osteric 通信通路的分析.
- 对联结体受体和联结体调节器相互作用的研究.
主要成果:
- 识别活跃与非活跃LRH-1连接体使用的独特的全信号电路.
- 不活跃的带利用强烈的,协调的动作进行AFS通信;激活的带破坏了这一点,并参与了第二个全位.
- 螺旋7中的联结体接触残留物对于这些通信电路之间的切换至关重要;不适当的联结体-同调器配对会导致不稳定的波动.
结论:
- 已经发现了LRH-1全信号传递的新特征,突出了连接体介导激活的独特途径.
- 这些发现表明,通过调节这些全oster电路来准LRH-1的潜在治疗策略.
- 定量模拟方法为研究其他核受体中的全信号提供了一个多功能框架.
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