评估一个剪接调节器的结合模式,刺激前mRNA与塑料U2AF2剪接因子结合
Riccardo Rozza1, Pavel Janoš1, Alessandra Magistrato1
1National Research Council of Italy (CNR)-Institute of Material Foundry (IOM) c/o International School for Advanced Studies (SISSA), Via Bonomea, 265, 34136 Trieste, Italy.
Journal of chemical information and modeling
|November 15, 2023
概括
用小分子准灵活的RNA识别动机 (RRMs) 是一个挑战. 动态对接揭示了NSC-194308如何稳定U2AF2-pre-mRNA结合,为新的癌症疗法提供了洞察力.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- RNA识别动机 (RRMs) 对于基因表达调节至关重要.
- 用小分子准动态RRM/RNA接口在药物发现中构成重大挑战.
- 具有灵活的RRM结构的U2AF2剪接因子结合了前mRNA聚胺序列.
研究的目的:
- 为了阐明U2AF2抑制剂NSC-194308.8.的结合模式.
- 了解NSC-194308诱导的U2AF2.2.上的mRNA前稳定的分子基础.
- 探索动态对接的适用性,以准灵活的蛋白质/RNA接口.
主要方法:
- 静态和动态对接方法的应用和基准测试.
- 推断出可信的NSC-194308绑定构成U2AF2.2. 的结论.
- 对推动mRNA前稳定性的分子相互作用的分析.
主要成果:
- 动态对接对于准确评估抑制剂与灵活的RRM架构的结合至关重要.
- 这项研究提供了关于NSC-194308作用的分子机制的见解.
- NSC-194308增强了对U2AF2的mRNA前结合,选择性地诱导白血病细胞死亡.
结论:
- 在针对塑料和模块化蛋白质/RNA接口时,必须考虑动态效应.
- 这些发现为开发针对蛋白质/蛋白质/RNA相互作用的治疗方法提供了广泛适用的机制.
- 这种方法可以指导用于选择性RNA功能调节的新药的发现.
相关概念视频
RNA Splicing
56.4K
Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
56.4K
Alternative RNA Splicing
21.2K
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
21.2K
Pre-mRNA Processing: RNA Splicing
5.3K
5.3K
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
920
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...
920
Pre-mRNA Processing: Modification of pre-mRNA Ends
9.3K
In eukaryotic cells, transcripts made by RNA polymerase are modified and processed before exiting the nucleus. Unprocessed RNA is called precursor mRNA or pre-mRNA to distinguish it from mature mRNA.
Once about 20-40 ribonucleotides have been joined together by RNA polymerase, a group of enzymes adds a cap to the 5' end of the growing transcript. In this process, a 5' phosphate is replaced by modified guanosine that has a methyl group attached (7-methyl guanosine). This 5' cap helps...
Once about 20-40 ribonucleotides have been joined together by RNA polymerase, a group of enzymes adds a cap to the 5' end of the growing transcript. In this process, a 5' phosphate is replaced by modified guanosine that has a methyl group attached (7-methyl guanosine). This 5' cap helps...
9.3K


