碳酸-NAD结合通过重塑形状可塑性和重新连接远程全网络来激活SIR2
Bao-Dan Zhang1,2,3, De-Rui Zhao1,2,3, Meng-Ting Liu1,2
1College of Agriculture and Biological Science, Dali University, Dali, China.
PLoS computational biology
|February 20, 2026
概括
这项研究揭示了辅因子与酵母SIR2的结合如何触发"核心锁定与外围释放"的动态模式,揭示了一个新的全osteric级联和长寿激活剂的可药物口袋.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 计算生物学 计算生物学
背景情况:
- 体调节允许蛋白质跨越距离传输信号,但机制往往不清楚.
- 酵母SIR2是一种依赖NAD+的脱乙酶,可以作为研究辅因子诱导的形状变化的模型.
研究的目的:
- 系统地阐明辅因子结合如何改变酵母SIR2的动态和内部通信.
- 为了确定涉及到全信号传输的分子通路.
- 探索潜在的可用药物的部位,以调节SIR2活性.
主要方法:
- 进行了多次3μs分子动力学模拟.
- 使用基于图形的深度学习模型 (神经关系推理).
- 进行信号通路分析,绘制通信网络的地图.
主要成果:
- 在辅助因子结合时,确定了一种可重现的"核心锁定与外围释放"动态模式.
- β1-α2循环变硬,而远端模块变得更加灵活.
- 发现新发现的"中继类型"残留物 (例如,Pro214,Thr224) 可以调解全级联.
- 发现了一个可用药物治疗的远端腔与继电器残留物重叠.
结论:
- 与SIR2结合的辅因子会诱导一种特定的动态模式,并建立一个新的继电器式全网络.
- 鉴定的腔体代表了开发小分子性激活剂的合理目标.
- 通过调节NAD+依赖性通路,准这种腔可以导致促进长寿的干预措施.
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