针对发现蛋白质相互作用稳定剂的基片查
Eline Sijbesma1, Kenneth K Hallenbeck2, Seppe Leysen1
1Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) , Eindhoven University of Technology , 5600 MB Eindhoven , The Netherlands.
Journal of the American Chemical Society
|February 2, 2019
概括
研究人员开发了一种新的结合方法来发现稳定蛋白与蛋白相互作用的小分子. 这项技术成功地确定了14-3-3σ和雌激素受体α相互作用的稳定剂,这在乳腺癌中至关重要.
科学领域:
- 药物发现和开发
- 分子生物学
- 结构生物学
背景情况:
- 用小分子调节蛋白-蛋白相互作用是药物发现的关键策略.
- 与抑制相比,PPI稳定具有优势,包括通过向特定蛋白界面来提高选择性.
研究的目的:
- 应用二硫化物捕获 (结) 选技术来识别稳定14-3-3σ和雌激素受体α (ERα) 相互作用的碎片.
- 探索PPI稳定作为乳腺癌的治疗策略,针对ERα的14-3-3σ调节.
主要方法:
- 使用定位二硫化物捕获 (结) 试验进行碎片选.
- 专注于14-3-3σ与ERα衍生之间的酸化依赖相互作用.
- 使用X射线结晶学确定稳定机制.
主要成果:
- 已确定可提高14-3-3σ/ERα亲和度的正经稳定剂,最高可增加40倍.
- 通过结构分析阐明了稳定机制.
- 与其他14-3-3客户端相比,对ERα类动机的部分选择性已被证明.
结论:
- 绑定方法对于发现PPI稳定剂是有效的.
- 这项研究为开发针对乳腺癌等疾病的新疗法提供了基础.
- PPI稳定是药物发现的一个有希望的,但未被充分探索的途径.
相关概念视频
Protein-protein Interfaces
14.7K
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...
14.7K
Protein and Protein Structure
87.4K
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...
87.4K
G-protein Coupled Receptors
132.0K
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
132.0K
What are Proteins?
238.8K
Overview
238.8K
Directing Proteins to the Rough Endoplasmic Reticulum
17.5K
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...
17.5K
Protein Networks
4.5K
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
4.5K


