DMDA-PatA通过将eIF4A和DDX3固定在GNG基因上来调解RNA序列选择性翻译抑制
Hironori Saito1,2, Yuma Handa3, Mingming Chen1,2
1RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
Nature communications
|September 2, 2024
概括
德甲基德萨米诺帕泰胺A (DMDA-PatA) 通过向eIF4A蛋白质,将其结到特定的RNA动机上,选择性地抑制蛋白质合成. 这一发现扩大了小分子在药物开发中的潜力.
科学领域:
- 分子生物学分子生物学
- 生物化学 生物化学
- 药物发现 药物发现 药物发现
背景情况:
- 选择性抑制mRNA翻译的小分子对于扩大可药物标具有价值.
- 很少有这样的化合物被确定,限制了它们的治疗潜力.
研究的目的:
- 识别和描述能够实现mRNA选择性翻译抑制的小分子.
- 阐明这些化合物抑制蛋白质合成的机制.
主要方法:
- 核糖体简介,以比较eIF4A抑制剂.
- 结合-n-Seq以确定RNA动机偏好.
- 分子动力学和量子化学计算.
- 开发一种不活跃的DMDA-PatA衍生物.
主要成果:
- 通过针对eIF4A,DMDA-PatA表现出独特的mRNA选择性来抑制翻译.
- 与DMDA-PatA结合的eIF4A优先结合NGRNA基因,而不依赖于ATP.
- 这种结合阻碍了核糖体扫描,DMDA-PatA上的正电荷诱导了G选择性.
- 确定DDX3是一种具有类似效果的替代DMDA-PatA标.
结论:
- DMDA-PatA为序列选择性RNA结合蛋白定提供了一种新的机制.
- 这项研究为药物开发提供了一种新的mRNA选择性蛋白质合成抑制剂类.
相关概念视频
Nonsense-mediated mRNA Decay
10.6K
The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
10.6K
Chromatin Structure Regulates pre-mRNA Processing
7.0K
In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
The chromatin structure, especially...
The chromatin structure, especially...
7.0K
Regulation of Expression at Multiple Steps
875
The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
875
Types of RNA
5.7K
Three main types of RNA are involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). These RNAs perform diverse functions and can be broadly classified as protein-coding or non-coding RNA. Non-coding RNAs play important roles in regulating gene expression in response to developmental and environmental changes. Non-coding RNAs in prokaryotes can be manipulated to develop more effective antibacterial drugs for human or animal use.
RNA Performs Diverse...
RNA Performs Diverse...
5.7K
Leaky Scanning
5.1K
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...
5.1K
Eukaryotic Transcription Inhibitors
9.8K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
9.8K


