在SARS-CoV-2RNA依赖RNA聚合酶中用于复制忠诚度控制的初始结合时捕获非同源核酸
Moises E Romero1, Shannon J McElhenney1, Jin Yu2
1Department of Chemistry, University of California, Irvine, CA 92697, USA.
Physical chemistry chemical physics : PCCP
|January 3, 2024
概括
SARS-CoV-2 RNA聚合酶通过区分正确与不正确的核酸来控制复制忠实度. 非同源核酸结合不稳定,防止病毒复制,并告知抗病毒药物设计.
科学领域:
- 分子生物学分子生物学
- 病毒学 病毒学
- 计算化学的计算化学
背景情况:
- 在SARS-CoV-2的RNA依赖RNA聚合酶 (RdRp) 对于病毒复制和转录至关重要.
- 了解RdRp的核酸选择性机制是控制病毒忠实性的关键.
研究的目的:
- 通过计算来研究 SARS-CoV-2 RdRp 在延长过程中的核酸选择性.
- 阐明相关与非相关核酸结合和插入的机制.
主要方法:
- 微秒整体平衡全原子分子动力学 (MD) 模拟.
- 改进的采样方法 (例如,总体采样) 来计算自由能源概况.
- 分析RdRp活性位点中的核酸结合和构造变化.
主要成果:
- 非同源的dATP和GTP在开放的活性部位中表现出稳定性,但无法插入.
- 相关的ATP和抗病毒药物模拟RDV-TP有利于在插入关闭的活性部位稳定.
- 通过不同的结合途径,SARS-CoV-2 RdRp 本质上拒绝非同源核酸.
结论:
- 这项研究揭示了SARS-CoV-2 RdRp的内在核酸选择性机制.
- 这种选择性机制有助于病毒基因组复制的真实性.
- 这些发现为设计针对RdRp功能的新型抗病毒药物提供了洞察力.
相关概念视频
01:43Proofreading
54.1K
Overview
54.1K
02:10Translesion DNA Polymerases
10.0K
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...
10.0K
00:43Bacterial RNA Polymerase
29.5K
Unlike eukaryotes, bacteria use a single RNA Polymerase (RNAP) to transcribe all genes. The different subunits of bacterial RNAPhave distinct functions. The multisubunit structure of the bacterial RNAP helps the enzyme to maintain catalytic function, facilitate assembly, interact with DNA and RNA, and self-regulate its activity.
In most genes, the transcription site is a single base present upstream of the coding sequence. Though RNAP is a catalytically efficient enzyme, it does not recognize...
In most genes, the transcription site is a single base present upstream of the coding sequence. Though RNAP is a catalytically efficient enzyme, it does not recognize...
29.5K
02:36RNA Polymerase II Accessory Proteins
9.2K
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
9.2K
00:58Eukaryotic RNA Polymerases
6.4K
6.4K
02:37Restarting Stalled Replication Forks
5.8K
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,...
5.8K