相关实验视频
Updated: Mar 15, 2026
15:49
Reverse Genetics to Engineer Positive-Sense RNA Virus Variants
Published on: June 9, 2022
2.0K
首选的remdesivir三酸盐由SARS-CoV-2聚合酶的结合被S759A突变改变为ATP
Calvin J Gordon1,2, Mizar F Oliva3, Hery W Lee1
1Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
Communications biology
|March 14, 2026
概括
雷梅西维尔三酸盐 (RTP) 最好通过SARS-CoV-2的RNA依赖RNA聚合酶 (RdRp) 结合,但连续的结合受到阻碍. 一种特定的RdRp突变 (S759A) 通过改变核酸结合和构造来赋予耐药性.
科学领域:
- 病毒学 病毒学
- 生物化学 生物化学
- 结构生物学 结构生物学
背景情况:
- 核类型是有效的抗病毒药物,dNTP类型作为DNA链终结剂.
- 通过延迟链终结或模板链嵌入,NTP模拟remdesivir抑制RNA合成.
研究的目的:
- 阐明SARS-CoV-2RNA依赖RNA聚合酶 (RdRp) 结合remdesivir三酸盐 (RTP) 的机制.
- 调查RTP公司注册偏好和连续注册的不利因素的结构性基础.
- 描述S759A突变对RdRp对RTP和ATP反应的影响.
主要方法:
- 酶分析被用来评估核酸的结合.
- 质谱法用于精确的分子分析.
- 确定了冷电子显微镜 (cryo-EM) 结构以可视化酶核酸相互作用.
主要成果:
- 在SARS-CoV-2中,RdRp优先结合RTP而不是ATP,即使ATP超过10倍.
- 结构数据显示,remdesivir:UMP基对中的构造限制阻碍了转位,限制了连续的RTP整合.
- S759A RdRp突变体表现出对RTP的抗性,有利于ATP的结合,这是由于原始3'-end核酸的重新定位和改变的核糖体构造.
结论:
- 雷梅西维尔的1'-基组施加一种构造限制,阻碍了RdRp转位,解释了相继RTP整合的减少.
- S759A突变改变了RdRp结构以抵抗RTP结合,突出了特定残留物在核酸选择性中的作用.
- 这些发现为设计具有独特抗病毒抑制机制的新型核类相应物提供了洞察力.
相关概念视频
00:36Viral Mutations
40.6K
A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
40.6K
02:10Translesion DNA Polymerases
11.5K
Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
11.5K
02:37Restarting Stalled Replication Forks
6.5K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
6.5K
01:43Proofreading
61.8K
Overview
61.8K