动机-VI循环在西尼罗河病毒NS3螺旋中充当核类
Priti Roy1, Zachary Walter2, Lauren Berish2
1Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.
Nucleic acids research
|June 17, 2024
概括
脊髓灰质炎病毒NS3螺旋酶 (NS3h) 对于病毒复制至关重要. 将其动机-VI循环 (MVIL) 作为分子为目标,为开发新抗病毒药物提供了一个有前途的战略.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 脊髓灰质炎病毒NS3螺旋酶 (NS3h) 对于病毒复制至关重要,也是潜在的药物标.
- NS3h使用ATP水解转移到核酸上,解开双链结构.
- 了解中间状态和构造变化是抑制剂发展的关键.
研究的目的:
- 在ATP水解周期期间模拟西尼罗河病毒NS3h的构造组合.
- 调查动机-VI循环 (MVIL) 在调节ATPase活性和病毒复制中的作用.
- 确定MVIL作为抗病毒药物开发的潜在目标.
主要方法:
- 在各种核酸结合状态 (apo,ATP,ADP+Pi,ADP) 中对NS3h进行了广泛的分子动力学模拟.
- 进行能量和结构聚类分析以表征构造组合.
- 创建和实验验证的MVIL突变 (D471L,D471N,D471E).
主要成果:
- 模拟显示了NS3h与ADP的差异性体亲和力,由MVIL调节.
- 与野生类型相比,MVIL突变体表现出显著降低的ATPase活性和RNA复制.
- 突变模拟显示了改变的MVIL构造,影响ATP结合和稳定.
结论:
- MVIL作为NS3h ATP口袋的依赖形状的"门".
- 针对MVIL是一个有前途的战略,用于开发针对Orthoflaviviruses的新型抗病毒疗法.
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