解密的秘密:形状和结构调节器如何抑制人类20S蛋白质组
Pedro M P Fernandes1,2,3, Romina A Guedes1,2,3, Bruno L Victor4
1Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Frontiers in chemistry
|January 23, 2024
概括
针对性治疗中的耐药性是一个挑战. 计算分析显示,人类蛋白质组中的Cys52Phe突变对药物结合产生了重大影响,为抗药机制提供了洞察力.
科学领域:
- 生物化学 生物化学
- 计算生物学 计算生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 对向疗法的获得性耐药性,特别是那些影响蛋白质功能 (如人体蛋白质组) 的耐药性,构成了重大的临床挑战.
- 预测由于特定蛋白质突变而导致的药物结合和耐药性对于有效的治疗策略至关重要.
研究的目的:
- 通过计算来研究人类蛋白质组活性部位中特定突变 (Ala49Thr,Ala50Val,Cys52Phe) 的影响.
- 了解这些突变如何影响蛋白质稳定性和药物相互作用,从而可能导致耐药性.
主要方法:
- 利用分子动力学模拟来分析蛋白质的稳定性.
- 采用分子对接计算来评估连接体结合亲和力.
- 专注于人类蛋白质组活性部位内的突变.
主要成果:
- 鉴定出Cys52Phe突变具有关键影响蛋白质 - 配体结合的特征.
- 评估了Ala49Thr和Ala50Val突变对蛋白质稳定性和药物相互作用的影响.
- 提供了关于特定突变如何改变药物疗效的见解.
结论:
- Cys52Phe突变显著破坏了药物与人体蛋白质组的结合.
- 这些发现为蛋白酶体抑制剂耐药性的机制提供了宝贵的见解.
- 强调计算方法在预测耐药性的重要性.
相关概念视频
The Proteasome Structure
757
The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
The proteasome is an...
757
The Proteasome
841
Eukaryotic cells can degrade proteins through several pathways. One of the most important among 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. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
841
Regulated Protein Degradation
7.3K
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...
7.3K
Covalently Linked Protein Regulators
6.8K
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....
6.8K
Regulation of Expression at Multiple Steps
910
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...
910
Regulation of Nuclear Protein Sorting
2.4K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.4K


