通过SARS-CoV-2复制酶进行基质选择的结构基础
Brandon F Malone1, Jason K Perry2, Paul Dominic B Olinares3
1Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA.
Nature
|February 1, 2023
概括
对SARS-CoV-2复制转录复合体 (RTC) 的结构洞察力揭示了它如何区分天然核酸,并结合了抗病毒药物remdesivir三酸盐 (RDV-TP). 这是新型抗病毒疗法设计的指导.
科学领域:
- 结构生物学
- 病毒学
- 药物发现
背景情况:
- SARS-CoV-2依赖RNA的RNA聚合酶 (RdRp) 形成了复制-转录复合体 (RTC),这是像雷梅西维尔这样的抗病毒药物的关键目标.
- 了解RTC如何选择核酸三酸盐 (NTP) 进行病毒RNA合成以及抗病毒药物如何竞争对于开发有效的抑制剂至关重要.
研究的目的:
- 阐明SARS-CoV-2 RTC识别自然NTP并结合抗病毒核酸类型的结构机制.
- 为选择性添加雷德西维三酸 (RDV-TP) 而不是腺三酸 (ATP) 提供结构基础.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 将RTC与自然NTP和RDV-TP复合进行可视化.
- 结构分析侧重于控制核酸结合和结合的相互作用.
主要成果:
- 获得了与自然NTP相关的RTC的详细结构.
- 揭示了RDV-TP选择性整合的结构基础,使其与ATP区分开来.
- 通过nsp12 NiRAN域进行核酸识别,包括对三酸 (GTP) 的选择性结合.
结论:
- 这些发现解释了NTP识别所必需的分子相互作用,为新型抗病毒药物的合理设计提供了信息.
- 对NiRAN域功能的洞察力支持其在5'RNA帽形成中的作用,这对病毒传播至关重要.
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