利用NMR组合异质性使小分子发现能够与动态蛋白质-蛋白质接口相对应
bioRxiv : the preprint server for biology
|February 12, 2026
概括
这项研究引入了AtlasNMR,这是一种新方法来发现针对动态蛋白相互作用的药物. 它确定了MC-3,一种破坏关键相互作用的小分子,并在疾病模型中显示神经保护作用.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 神经科学是一个神经科学.
背景情况:
- 涉及动态域的蛋白质与蛋白质相互作用是具有挑战性的药物标.
- 静态结构往往错过了异质蛋白质中关键的带结合状态.
研究的目的:
- 开发一个计算框架,AtlasNMR,用于针对动态蛋白界面的小分子发现.
- 为了确定神经元氧化合成酶 (nNOS) PDZ域相互作用的调节剂与CAPON.
主要方法:
- 利用阿特拉斯NMR分析多模型的NMR集,产生构造假设.
- 进行了基于集体的虚拟选和共识排名.
- 在细胞和与疾病相关的神经元模型中测试了已识别的小分子 (MC-3).
主要成果:
- 阿特拉斯NMR从nNOS PDZ域NMR组合中确定了两个关键的构造状态.
- 组合查产生了MC-3,一种破坏nNOS-CAPON相互作用的新型小分子.
- MC-3通过减少细胞毒性,化应激和陶酸化来显示神经保护作用.
结论:
- 阿特拉斯NMR提供了使用NMR数据对动态蛋白界面进行药物发现的可概括策略.
- MC-3是一种有前途的化合物,在神经退行性疾病中具有治疗潜力.
- 利用蛋白质结构异质性是针对具有挑战性的蛋白质-蛋白质相互作用的关键.
相关概念视频
Protein-protein Interfaces
14.8K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
14.8K
Protein-Protein Interfaces
4.5K
4.5K
Protein Dynamics in Living Cells
2.7K
Different fluorescence-based techniques are used to study the protein dynamics in living cells. These techniques include FRAP, FRET, and PET.
Fluorescent recovery after photobleaching (FRAP) is a fluorescent-protein-based detection technique used to quantify protein movement rates within the cell. This method exposes a small portion of the cell to an intense laser beam. The laser beam causes permanent photobleaching of the fluorophore-tagged proteins in the exposed region. As the bleached...
Fluorescent recovery after photobleaching (FRAP) is a fluorescent-protein-based detection technique used to quantify protein movement rates within the cell. This method exposes a small portion of the cell to an intense laser beam. The laser beam causes permanent photobleaching of the fluorophore-tagged proteins in the exposed region. As the bleached...
2.7K
¹H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR
1.7K
The axial and equatorial protons in cyclohexane can be distinguished by performing a variable-temperature NMR experiment. In this process, except for one proton, the remaining eleven protons are replaced by deuterium. The deuterium substitution avoids the possible peak splitting caused by the spin-spin coupling between the adjacent protons. The remaining proton flips between the axial and equatorial positions.
1.7K
Mechanical Protein Functions
5.7K
Proteins perform many mechanical functions in a cell. These proteins can be classified into two general categories- proteins that generate mechanical forces and proteins that are subjected to mechanical forces. Proteins providing mechanical support to the structure of the cell, such as keratin, are subjected to mechanical force, whereas proteins involved in cell movement and transport of molecules across cell membranes, such as an ion pump, are examples of generating mechanical force.
5.7K
Protein and Protein Structure
88.9K
Proteins are one of the most abundant organic molecules in living systems and have the most diverse range of functions of all macromolecules. Proteins may be structural, regulatory, contractile, or protective. They may serve in transport, storage, or membranes; or they may be toxins or enzymes. Their structures, like their functions, vary greatly. They are all, however, amino acid polymers arranged in a linear sequence.
A protein's shape is critical to its function. For example, an enzyme...
A protein's shape is critical to its function. For example, an enzyme...
88.9K


