扩展RNA CAG重复的动态结构模型:精细的X射线结构和使用分子动力学和雨采样模拟的计算调查
Ilyas Yildirim1, HaJeung Park, Matthew D Disney
1Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States. i-yildirim@northwestern.edu
Journal of the American Chemical Society
|February 28, 2013
概括
重复的RNA转录,就像扩展的CAG重复一样,可以引起疾病. 这项研究揭示了这些RNA重复的结构动态,表明它们可以采用不同的构造,影响疾病机制和潜在的治疗点.
科学领域:
- 结构生物学 结构生物学
- 计算生物学 计算生物学
- 在RNA治疗方面,RNA疗法.
背景情况:
- 重复RNA转录与包括亨廷顿病在内的各种疾病有关,通常通过产生有毒蛋白质.
- 扩展的CAG重复是导致疾病的RNA序列的一个关键例子.
研究的目的:
- 为了阐明CAG扩展RNA重复的结构构造和动态.
- 了解RNA结构,动态和疾病机制之间的关系.
- 为了确定小分子治疗的潜在目标.
主要方法:
- 进行X射线晶体学以确定高分辨率RNA结构.
- 在明确溶剂中进行分子动力学 (MD) 模拟,以分析RNA动力学.
- 雨采样模拟以调查构造变化和自由能源景观.
主要成果:
- 一个CAG重复模型的晶体结构 (r[5'UUGGGC(CAG) 3GUCC]2) 显示了内部循环的反反和同反方向.
- MD模拟显示了反抗和同抗基对的稳定性,而反抗基对是动态的.
- 模拟确定了从syn-anti到anti-conformations的转换途径,与雨采样预测一致,以及在syn-anti conformations附近的绑定口袋.
结论:
- 在CAG重复中,1x1核酸AA内部循环的全球最小构造是anti-anti,但根据分子环境可以获得syn-anti构造.
- 了解这些RNA动态组合对于RNA动态-功能关系至关重要.
- 这些发现可以为小分子的开发提供信息,以治疗目的准RNA动态组合.
相关概念视频
RNA Structure
Overview
The basic structure of RNA consists of a five-carbon sugar and one of four nitrogenous bases. Although most RNA is single-stranded, it can form complex secondary and tertiary structures. Such structures play essential roles in the regulation of transcription and translation.
Different Types of RNA Have the Same Basic Structure
There are three main types of ribonucleic acid (RNA): messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). All three RNA types consist of a...
The basic structure of RNA consists of a five-carbon sugar and one of four nitrogenous bases. Although most RNA is single-stranded, it can form complex secondary and tertiary structures. Such structures play essential roles in the regulation of transcription and translation.
Different Types of RNA Have the Same Basic Structure
There are three main types of ribonucleic acid (RNA): messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). All three RNA types consist of a...
RNA Structure
The basic structure of RNA consists of a string of ribonucleotides attached by phosphodiester bonds. Although most RNA is single-stranded, it can form complex secondary and tertiary structures. Such structures play essential roles in the regulation of transcription and translation.
Different Types of RNA Have the Same Basic Structure
There are three main types of ribonucleic acid (RNA) involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). All three...
Different Types of RNA Have the Same Basic Structure
There are three main types of ribonucleic acid (RNA) involved in protein synthesis: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). All three...
RNA Structure
Overview
The basic structure of RNA consists of a five-carbon sugar and one of four nitrogenous bases. Although most RNA is single-stranded, it can form complex secondary and tertiary structures. Such structures play essential roles in the regulation of transcription and translation.
Different Types of RNA Have the Same Basic Structure
There are three main types of ribonucleic acid (RNA): messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). All three RNA types consist of a...
The basic structure of RNA consists of a five-carbon sugar and one of four nitrogenous bases. Although most RNA is single-stranded, it can form complex secondary and tertiary structures. Such structures play essential roles in the regulation of transcription and translation.
Different Types of RNA Have the Same Basic Structure
There are three main types of ribonucleic acid (RNA): messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). All three RNA types consist of a...
Nucleic Acid Structure
The pentose sugar in DNA is deoxyribose, while in RNA the pentose sugar is ribose. The difference between the sugars is the presence of the hydroxyl group on the ribose's second carbon and a hydrogen on the deoxyribose's second carbon. The phosphate residue attaches to the hydroxyl group of the 5′ carbon of one sugar and the hydroxyl group of the 3′ carbon of the sugar of the next nucleotide, which forms a 5′ to 3′ phosphodiester linkage.
DNA Structure
DNA has a double-helix structure. The...
DNA Structure
DNA has a double-helix structure. The...
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...
The DNA Helix
Deoxyribonucleic acid, or DNA, is the genetic material responsible for passing traits from generation to generation in all organisms and most viruses. DNA is composed of two strands of nucleotides that wind around each other to form a spring-like structure called a double helix. However, the double helix is not perfectly symmetrical. Instead, there are regularly occurring grooves in the structure. The major groove occurs where the sugar-phosphate backbones are relatively far apart. This space...


