一个电荷驱动的策略对生物分子凝聚物的共价修饰和调节
Zhewei Chen1, Lu Liu1, Jerome Cattin2
1Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Journal of the American Chemical Society
|August 2, 2025
概括
研究人员开发了一种新的电荷驱动策略,以抑制生物分子凝聚物形成,准Ras GTPase激活蛋白结合蛋白1 (G3BP1),以防止压力颗粒组装,提供一种新的治疗方法.
科学领域:
- 生物化学
- 分子生物学
- 化学生物学
背景情况:
- 生物分子凝聚物是关键的细胞结构,
- 通过小分子直接向介导凝聚物形成的蛋白质是具有挑战性的.
- 拉斯GTPase激活蛋白结合蛋白1 (G3BP1) 是压力颗粒 (SG) 形成的关键蛋白.
研究的目的:
- 提出一种新的电荷驱动策略来调节生物分子凝聚物形成.
- 证明该策略在抑制G3BP1介导的压力颗粒形成中的应用.
- 探索针对G3BP1的小分子抑制剂的作用机制.
主要方法:
- 使用碳酸胺共价功能的小分子SG抑制剂的开发.
- 修改G3BP1的折叠域以引入表面电荷.
- 使用表达氨酸突变G3BP1的HeLa细胞进行细胞实验.
- 进行结构活动关系研究和分子动力学模拟.
主要成果:
- G3BP1的小分子修饰改变了内在无序区域的结构动态.
- 细胞实验和SAR研究支持建议的电荷驱动机制.
- 分子动力学模拟表明转向更紧的G3BP1形状.
结论:
- 建立了一个新的电荷驱动策略,用于合理调节生物分子凝聚物.
- 证明了这种策略可以抑制G3BP1介导的压力颗粒形成.
- 提供了小分子G3BP1修饰引起的构造变化.
相关概念视频
Covalently Linked Protein Regulators
7.2K
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....
7.2K
Noncovalent Attractions in Biomolecules
54.9K
Noncovalent attractions are associations within and between molecules that influence the shape and structural stability of complexes. These interactions differ from covalent bonding in that they do not involve sharing of electrons.
Four types of noncovalent interactions are hydrogen bonds, van der Waals forces, ionic bonds, and hydrophobic interactions.
Hydrogen bonding results from the electrostatic attraction of a hydrogen atom covalently bonded to a strong-electronegative atom like oxygen,...
Four types of noncovalent interactions are hydrogen bonds, van der Waals forces, ionic bonds, and hydrophobic interactions.
Hydrogen bonding results from the electrostatic attraction of a hydrogen atom covalently bonded to a strong-electronegative atom like oxygen,...
54.9K
Cationic Chain-Growth Polymerization: Mechanism
2.4K
The cationic polymerization mechanism consists of three steps: initiation, propagation, and termination. In the initiation step of the polymerization process, the π bond of a monomer gets protonated by the Lewis acid catalyst, which is formed from boron trifluoride and water. The protonation of the π bond generates a carbocation stabilized by the electron‐donating group. In the propagation step, the π bond of the second monomer acts as a nucleophile and attacks the...
2.4K
Cooperative Allosteric Transitions
2.4K
2.4K


