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在西尼罗河病毒NS3螺旋酶中通过V-VI合的动机对RNA亲和力的异构调节

Priti Roy¹, Martin McCullagh¹

¹Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma, USA.

|January 20, 2026

概括

西尼罗病毒非结构性蛋白3酶 (NS3h) 使用一种依赖ATP的机制来控制RNA结合,这对于病毒复制至关重要. 了解这种相互作用为抗黄病毒病毒的抗病毒药物开发提供了新的目标.

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:

像西尼罗河病毒 (WNV) 这样的 Flaviviral 疾病是一个日益严重的全球健康问题.
WNV非结构性蛋白3酶 (NS3h) 对于病毒复制至关重要,也是关键的抗病毒标.
之前的工作确定了WNV NS3h中的动图VI循环 (VIL) 作为调节ADP亲和力的核.

研究的目的:

为了研究VIL核酸结合和RNA结合在WNV NS3h中的IVa/V基因之间的合.
阐明由NS3h.介导的单链RNA (ssRNA) 转位的机制.
为了确定针对NS3h功能的基于结构的抗病毒干预点.

主要方法:

微秒级全原子分子动力学模拟 WNV NS3h 水解中间体.
蛋白质-核酸和蛋白质-RNA相互作用的结构分析.
将分子动力学发现与VIL突变体的现有实验数据相关联.

主要成果:

一个依赖ATP的合机制将VIL中的核酸亲和关系与IVa/V动机中的RNA亲和关系联系起来.
关键的VIL残留物 (R461,R464) 直接影响在动机V的RNA酸盐亲和力.
在E413 (动因V) 和R461 (VIL) 之间的ATP敏感相互作用调节动因V3₁₀-螺旋,影响RNA结合.
这种相互作用在具有催化缺陷的VIL突变体中被破坏,与受损的水解和病毒复制有关.

结论:

WNV NS3h采用了一种协调的ssRNA转位机制,通过依赖ATP的形状变化来调节.
VIL和IVa/V基因之间的相互作用对NS3h酶活性和病毒复制至关重要.
这些发现揭示了对NS3h功能的新见解,并为基于结构的抗病毒药物设计针对黄病毒病毒提供了机会.

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