通过ATP竞争性抑制剂和ERK2中的全osteric通讯进行对形选择
Jake W Anderson1, David Vaisar1, David N Jones2
1Department of Biochemistry, University of Colorado, Boulder, United States.
eLife
|March 27, 2024
概括
研究人员发现了新的细胞外信号调节激酶-2 (ERK2) 抑制剂,可选择活性R状态. 这些分子揭示了全效应如何调节激酶动态和基质相互作用.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 细胞外信号调节激酶-2 (ERK2) 激活涉及动态形状变化.
- 活性"R状态"与有效的ATP结合有关,但驱动抑制剂选择的特征尚不清楚.
研究的目的:
- 识别具有R状态选择性质的新型ATP竞争性ERK抑制剂.
- 阐明ERK2.2中抑制剂诱导的R状态选择的结构和动态特征.
主要方法:
- -交换质谱法 (HDX-MS) 是一种质谱法.
- 进行NMR放松分散测量.
- 在X射线晶体学.
主要成果:
- 确定了14种表现出R状态选择的新ERK抑制剂.
- 抑制剂在激活循环,P+1,螺旋αF和螺旋αL16.16上诱导了全效应.
- 晶体结构透露了通过特定相互作用在Gly循环和环αC中受抑制剂介导的转移.
结论:
- 提出了一个R状态的模型,涉及N叶运动和活性部位的紧性.
- 抑制剂的形状选择特性可以调节ERK基质对接接口.
- 结果为设计有针对性的ERK调制器提供了洞察力.
相关概念视频
Allosteric Regulation
57.9K
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
57.9K
Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
Amplifying Signals via Enzymatic Cascade
8.5K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.5K
Cooperative Allosteric Transitions
2.3K
2.3K
Enzyme-linked Receptors
78.3K
Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
78.3K
Transducer Mechanism: Enzyme-Linked Receptors
2.5K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.5K


