De novo 设计的Ras同型选择性结合剂的设计
Jason Z Zhang1,2,3, Xinting Li1,2, Alexa Rane Batingana4
1Department of Biochemistry, University of Washington, Seattle, Washington 98195, United States.
bioRxiv : the preprint server for biology
|February 20, 2025
概括
研究人员使用深度学习开发了新的Ras异型特异性结合剂 (RIBs). 这些结合剂向Ras C末端,使得研究Ras异型在癌症和细胞通路中的不同角色成为可能.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 生物信息学是一种生物信息学.
- 蛋白质工程是指蛋白质工程.
背景情况:
- 原型瘤基因Ras调节关键的细胞内通路,其中四种主要异型 (KRAS4A,KRAS4B,HRAS和NRAS) 呈现出高序列同质性.
- 由于它们与不同癌症的多种关联,研究个别的Ras异形函数至关重要.
- 拉斯研究的一个显著的局限性是异型特异性结合试剂的稀缺性,主要是由于针对它们不同的C-终端的挑战.
研究的目的:
- 为了克服Ras蛋白质缺少异型特异性试剂.
- 设计和验证新的结合分子,专门针对Ras异型的C-末端.
- 为了能够剖析单个Ras异型的独特的生物学和病理作用.
主要方法:
- 利用基于深度学习的方法来*de novo*设计蛋白质结合剂.
- 工程化Ras异型特异性结合剂 (RIBs) 针对KRAS4A,KRAS4B,HRAS和NRAS的独特C终端区域.
- 验证了设计的RIBs的特异性和功能 *in vitro* 和细胞模型.
主要成果:
- 成功设计并产生了针对Ras C终端的Ras异型特异性结合剂 (RIBs).
- 证明了RIBs对它们的同类Ras异型的高特异性,无论是*in vitro*还是细胞内.
- 观察到RIBs破坏Ras膜局部化并抑制Ras活动,证实了它们的功能影响.
结论:
- 深度学习允许*de novo*设计高度特定的蛋白质结合剂,以应对具有挑战性的目标,如Ras C-termini.
- 开发的RIB是区分Ras异型体在生物过程中的功能有价值的工具.
- 这些RIB有潜力推进研究Ras驱动的疾病,包括各种癌症.
更多相关视频
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
11.3K
08:09Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice
Published on: March 24, 2017
8.0K
相关概念视频
01:28Structure-Activity Relationships and Drug Design
488
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
488
01:24Small GTPases - Ras and Rho
3.9K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
3.9K
01:29The Two-State Receptor Model
1.9K
The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
The binding affinity of a drug determines its interaction with...
1.9K
01:49Conserved Binding Sites
4.1K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.1K
00:49Ligand Binding and Linkage
4.7K
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...
4.7K
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
2.5K
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
2.5K