基于结构的设计,用光胺掩盖的共价联体向E3联酶SOCS2的向
Sarath Ramachandran1, Nikolai Makukhin1,2, Kevin Haubrich1
1Centre for Targeted Protein Degradation, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee, DD1 5JJ, United Kingdom.
Nature communications
|October 10, 2023
概括
研究人员开发了针对SOCS2 E3结合酶的新型共价抑制剂.
科学领域:
- 生物化学 生物化学
- 化学生物学 化学生物学
- 药物发现 药物发现 药物发现
背景情况:
- Src同质性2 (SH2) 域与酸铁 (pY) 修饰结合,对于细胞信号传递至关重要.
- 开发用于SH2域的药物是具有挑战性的,因为pY及其模拟物的特性.
- 细胞因子信号传递2抑制剂 (SOCS2) 是一种E3结合酶,具有SH2域参与信号通路.
研究的目的:
- 设计和开发针对SOCS2.2的SH2域的新型,细胞透的共价抑制剂.
- 为了利用基于结构的设计和碎片生长来开发抑制剂.
- 探索SOCS2抑制剂作为化学探针和PROTAC中的实用性.
主要方法:
- 基于结构的药物设计和碎片成长的方法.
- 针对Cys111.1.的共价变异策略.
- 合成前药物MN714与一个POM保护组.
- 细胞向参与和细胞内19FNMR光谱学.
主要成果:
- 鉴定一种氨酸导向的电友共价抑制剂 (MN551) 向SOCS2.2.
- 对MN714的细胞透性和前药物揭露的演示.
- 在Cys111中确认了共价接触,阻止了SOCS2基质的招募.
- 竞争性抑制SOCS2蛋白与其原生基质结合.
结论:
- 成功设计和合成了SOCS2的新型共价抑制剂.
- 开发的抑制剂具有细胞透性,并有效地参与SOCS2标.
- 这些抑制剂作为SOCS2生物学的化学探针和作为PROTACs的组件具有前景.
相关概念视频
00:49Ligand Binding and Linkage
4.8K
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...
4.8K
01:30Assembly of Signaling Complexes
5.8K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
5.8K
02:40Ligand Binding Sites
12.9K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.9K
02:04Covalently Linked Protein Regulators
6.8K
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....
6.8K