酸修饰治疗核酸对蛋白质的增加亲和力的起源
Malwina Hyjek-Składanowska1,2, Timothy A Vickers3, Agnieszka Napiórkowska1,2
1Structural Biology Center, International Institute of Molecular and Cell Biology, 4 Trojdena St., 02-109 Warsaw, Poland.
Journal of the American Chemical Society
|March 24, 2020
概括
酸 (PS) 的修饰增强了核酸药物特性. 这项研究揭示了与完全PS核酸结合的蛋白质的第一个晶体结构,详细介绍了相互作用及其对药物设计的影响.
科学领域:
- 生物化学
- 结构生物学
- 药物发现
背景情况:
- 酸 (PS) 骨干修饰对于增强抗意义寡核酸 (ASO) 等核酸药物的治疗性质至关重要.
- 改善了代谢稳定性和蛋白质相互作用,帮助组织分布和细胞吸收.
- 这些PS核酸与蛋白质之间的增强相互作用的结构基础在很大程度上仍未被探索.
研究的目的:
- 阐明酸改性核酸与蛋白质之间相互作用的结构机制.
- 确定与完全PS核酸复合的蛋白质的第一个晶体结构.
主要方法:
- 使用X射线结晶学来确定PC4蛋白的DNA结合域的结构,并使用完整的PS2'-OMeDNA间隙 ASO.
- 使用NanoBRET结合试验证实了蛋白质与核酸接触的重要性.
主要成果:
- 这项研究报告了第一个与完全PS核酸结合的蛋白质 (PC4) 的晶体结构.
- ASO采用了类似发针的结构,不同的PC4接口连接了ASO的不同区域.
- PC4形成了二元体的二元体,通过绑定ASO之间的合稳定,并通过静电和疏水力与PS骨干相互作用.
结论:
- 这些发现为PS ASO与蛋白质之间的相互作用提供了原子层面的洞察力,解释了增强的亲和力.
- 这项研究提供了PS ASO蛋白相互作用如何影响蛋白蛋白相互作用和细胞毒性的结构模型.
- 这种结构理解可以指导下一代核酸治疗的合理设计.
相关概念视频
Covalently Linked Protein Regulators
8.5K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
8.5K
Phosphodiester Linkages
109.3K
Overview
Phosphodiester bond forms when a phosphoric acid molecule (H3PO4) links with two hydroxyl groups (–OH) of two other molecules, forming two ester bonds. Two water molecules are released in this process. The phosphodiester bond is commonly found in nucleic acids (DNA and RNA) and plays a critical role in their structure and function.
Phosphodiester Bonds Link Nucleotides Together
DNA and RNA are polynucleotides or long chains of nucleotides that are linked together. A nucleotide is...
Phosphodiester bond forms when a phosphoric acid molecule (H3PO4) links with two hydroxyl groups (–OH) of two other molecules, forming two ester bonds. Two water molecules are released in this process. The phosphodiester bond is commonly found in nucleic acids (DNA and RNA) and plays a critical role in their structure and function.
Phosphodiester Bonds Link Nucleotides Together
DNA and RNA are polynucleotides or long chains of nucleotides that are linked together. A nucleotide is...
109.3K
Phosphorylation
53.4K
The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...
53.4K
Ligand Binding and Linkage
5.4K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
5.4K
Transfer RNA Synthesis
13.0K
One of the unique features of tRNA is the presence of modified bases. In some tRNAs, modified bases account for nearly 20% of the total bases in the molecule. Altogether, these unusual bases protect the tRNA from enzymatic degradation by RNases.
Each of these chemical modifications is carried by a specific enzyme, post-transcription. All of these enzymes have unique base and site-specificity. Methylation, the most common chemical modification, is carried by at least nine different enzymes, with...
Each of these chemical modifications is carried by a specific enzyme, post-transcription. All of these enzymes have unique base and site-specificity. Methylation, the most common chemical modification, is carried by at least nine different enzymes, with...
13.0K
Protein Kinases and Phosphatases
14.7K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
14.7K


