铜(II) 协调到SARS-CoV-2 Nsp1的内在无序区域
Maryann Morales1, Moon Young Yang1, William A Goddard1
1Beckman Institute, California Institute of Technology, Pasadena, CA 91125.
概括
严重急性呼吸道综合征冠状病毒2 (SARS-CoV-2) Nsp1-CT蛋白抑制宿主蛋白质的合成. 铜 (II) 离子与该结合,有可能在感染期间恢复蛋白质合成.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 病毒学 病毒学
背景情况:
- 严重急性呼吸道综合征冠状病毒2 (SARS-CoV-2) 非结构蛋白-1 (Nsp1-CT) 是一个内在失调的区域.
- Nsp1-CT通过阻断信使RNA (mRNA) 进入40S核糖体入口道来抑制宿主蛋白质合成.
研究的目的:
- 调查铜 (II) 离子恢复宿主蛋白质合成的潜力,这种合成被SARS-CoV-2 Nsp1-CT抑制.
- 阐明铜 (II) -Nsp1-CT相互作用的结合机制和结构特征.
主要方法:
- 电子偏磁共振 (EPR) 谱学和托芬光测量在一个10残留模型 (Nsp1-CT10) 上进行.
- 使用先进的量子力学计算来建模铜 (II) 复合体.
- 计算模型通过将模拟的EPR光谱与实验数据进行比较来验证.
主要成果:
- 水性铜 (II) 离子与Nsp1-CT结合,具有微分子亲和力.
- 这种可以作为铜的多联体 (multidentate ligand).
- 开发了两个不同的铜II-复合物的计算模型,代表不同的pH条件 (pH6.5和pH7.5-8.5).
- 来自计算模型的模拟EPR光谱与实验EPR光谱有很好的一致性.
结论:
- 铜对Nsp1-CT的结合提供了一种潜在的治疗策略,以抵消SARS-CoV-2诱导的宿主蛋白质合成抑制.
- 这项研究提供了详细的结构洞察力,以分子层面的铜(II) -Nsp1-CT相互作用.
- 这些发现支持使用生物物理和计算方法来表征与病毒病原性相关的蛋白质金属离子相互作用.
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