连接到清理策略使得有针对性的蛋白质降解能够按需终止
Yuhui Jin1,2, Jing Fan1,2, Ruyan Wang1,2
1Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University; Nanjing 210009, China.
Journal of the American Chemical Society
|March 27, 2023
概括
研究人员开发了一种新的"连接到清理"系统来控制化向化体 (PROTAC) 的降解. 这种方法使用TCO修饰的树状分子来清理PROTAC,从而在活细胞中实现按需的蛋白质淘汰.
科学领域:
- 生物化学
- 化学生物学
- 分子生物学
背景情况:
- 针对蛋白质降解 (PROTAC) 技术利用双功能分子进行向蛋白质降解.
- 通过催化机制起作用,导致目标蛋白质的多个降解周期.
- 控制PROTAC中介降解的持续时间和程度仍然是一个挑战.
研究的目的:
- 开发一种新的化学方法来终止事件驱动的蛋白质降解.
- 引入一个"绑定到清理"系统来控制活细胞中的蛋白质水平.
- 为了实现对感兴趣的蛋白质 (POI) 的按需化学淘汰.
主要方法:
- 作为清除剂的TCO修饰型树脂分子 (PAMAM-G5-TCO) 的设计和合成.
- 用氨酸修饰的PROTAC (Tz-PROTAC) 的开发.
- 使用反向电子需求迪尔斯-阿尔德反应快速清理细胞内的自由PROTAC.
主要成果:
- 该系统有效地终止了活细胞中PROTAC诱导的降解.
- 通过生物直角点击化学反应,PAMAM-G5-TCO快速清除自由的Tz-PROTAC.
- 证明精确控制受关注蛋白质 (POI) 要求的水平.
结论:
- "连接到清理"的方法提供了一种多功能策略来终止事件驱动的退化.
- 这种方法为精确控制蛋白质水平提供了灵活的化学敲击工具.
- 在受控目标蛋白质降解研究中为先进应用铺平了道路.
相关概念视频
Regulated Protein Degradation
7.4K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.4K
Export of Misfolded Proteins out of the ER
3.7K
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.7K
The Proteasome
8.8K
Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
8.8K
ER Retrieval Pathway
3.9K
In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
3.9K
Directing Proteins to the Rough Endoplasmic Reticulum
7.3K
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
7.3K
Tagging and Fusion Proteins
6.8K
Proteins are involved in several cellular processes and biochemical reactions. Analyzing a specific protein of interest requires it to be isolated from the other proteins in the cell. This is achieved by overexpressing the specific gene in a suitable host to produce large quantities of the target protein. A tag or label is recombined with the gene to produce a fusion protein containing the target protein and the tag. The tags on these fusion proteins can then be used for easy detection and...
6.8K


