通过双向全路径对ClpP活性进行小分子失调
Marim M Barghash1, Mark F Mabanglo1, Samuel E Hoff2
1Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada.
Structure (London, England : 1993)
|August 12, 2025
概括
激活细菌ClpP蛋白酶的小分子对于病原体毒性至关重要,可以在内部或外部结合. 这项研究揭示了ClpP全激活的常见途径,导致蛋白酶失调和潜在的抗菌策略.
科学领域:
- 微生物学 微生物学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 细菌ClpP蛋白酶对于人类病原体的毒性和感染性至关重要.
- ClpP是一种经过验证的抗菌药物标,已知小分子调节其活性.
研究的目的:
- 阐明小分子通过ClpP激活的机制.
- 通过不同类的效应因子来确定ClpP全激活的常见途径.
主要方法:
- 综合性方法结合了结构,生化和计算分析.
- 识别和描述与ClpP结合的小分子.
主要成果:
- 发现小分子通过与内部催化部位结合来激活ClpP.
- 通过特定位点的效应因子确定了ClpP全激活的常见分子通路.
- 提出了一个共识,双向的ClpP激活机制.
结论:
- 了解ClpP激活机制,可以了解蛋白酶失调的情况.
- 已识别的途径为开发针对ClpP的抗菌剂提供了新的策略.
相关概念视频
Allosteric Regulation
59.0K
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
59.0K
Cooperative Allosteric Transitions
8.0K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
8.0K
Allosteric Proteins-ATCase
5.9K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.9K
Coordination of Gene Expression Processes in Bacteria
148
The DNA replication, transcription, and translation processes are intricately coupled in bacteria, allowing efficient gene expression and rapid protein synthesis. While this physical and functional coordination is advantageous, it introduces challenges that bacteria overcome through specific regulatory mechanisms.Coupling of Replication, Transcription, and TranslationThe coupling of replication, transcription, and translation is a hallmark of bacterial gene expression. As the replisome unwinds...
148
Ligand Binding and Linkage
4.9K
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...
4.9K
Membrane Asymmetry Regulating Transporters
4.9K
Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
4.9K


