流感病毒RNA聚合酶中一个基本子单元相互作用的结构基础
Eiji Obayashi1, Hisashi Yoshida, Fumihiro Kawai
1Protein Design Laboratory, Yokohama City University, 1-7-29 Suehiro, Tsurumi, Yokohama 230-0045, Japan.
Nature
|July 29, 2008
概括
针对病毒RNA聚合酶复合物的新型流感A病毒治疗可能会出现. 研究人员阐明了一个关键的子单元接口,揭示了新的药物结合部位,独立于抗病毒开发的表面抗原.
科学领域:
- 病毒学 病毒学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 流感A型病毒由于快速突变和潜在的流行病,造成了全球健康的重大威胁.
- 现有的治疗方法有限,迫切需要新的抗病毒策略.
- 病毒RNA聚合酶复合体对于流感复制是必不可少的,但在结构上仍然很大程度上没有特征.
研究的目的:
- 为了研究甲型流感病毒RNA聚合酶复合物的结构基础.
- 在聚合酶复合体内识别潜在的新药标.
- 为抗病毒药物设计提供对子单元相互作用的结构性见解.
主要方法:
- 结晶学被用来确定由流感ARNA聚合酶PA和PB1亚单元的碎片组成的复合物的结构.
- 分析PA和PB1亚单元之间的蛋白质-蛋白质接口.
主要成果:
- 晶体结构揭示了PA子单元的碳氧终端域中的新折叠.
- 在PA子单元上发现了一个深厚的疏水槽,容纳了PB1子单元的氨基末端残留物.
- 这种相互作用在病毒RNA聚合酶中形成了一个关键的子单元接口.
结论:
- 阐明的PA-PB1接口代表了针对流感A病毒的抗病毒药物开发的新目标.
- 这个目标独立于病毒表面抗原,提供了一种克服免疫逃避的策略.
- 对聚合酶复合物的结构信息对于设计有效的流感治疗方法至关重要.
相关概念视频
Eukaryotic RNA Polymerases
RNA Polymerase (RNAP) is conserved in all animals, with bacterial, archaeal, and eukaryotic RNAPs sharing significant sequence, structural, and functional similarities. Among the three eukaryotic RNAPs, RNA Polymerase II is most similar to bacterial RNAP in terms of both structural organization and folding topologies of the enzyme subunits. However, these similarities are not reflected in their mechanism of action.
All three eukaryotic RNAPs require specific transcription factors, of which the...
All three eukaryotic RNAPs require specific transcription factors, of which the...
RNA Polymerase II Accessory Proteins
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...
Leaky Scanning
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R stands for...
Transcription Initiation
Initiation is the first step of transcription in eukaryotes. Prokaryotic RNA Polymerase (RNAP) can bind to the template DNA and start transcribing. On the other hand, transcription in eukaryotes requires additional proteins, called transcription factors, to first bind to the promoter region in the DNA template. This binding helps recruit the specific RNAP that can assemble on the DNA and start transcription.
The promoters and enhancers and their accessory proteins allow tight regulation of...
The promoters and enhancers and their accessory proteins allow tight regulation of...
Eukaryotic RNA Polymerases
RNA Polymerase (RNAP) is conserved in all animals, with bacterial, archaeal, and eukaryotic RNAPs sharing significant sequence, structural, and functional similarities. Among the three eukaryotic RNAPs, RNA Polymerase II is most similar to bacterial RNAP in terms of both structural organization and folding topologies of the enzyme subunits. However, these similarities are not reflected in their mechanism of action.
All three eukaryotic RNAPs require specific transcription factors, of which the...
All three eukaryotic RNAPs require specific transcription factors, of which the...
RNA Polymerase II Accessory Proteins
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...


