多种功能蛋白质-蛋白质相互作用接口 整体调节在循环素依赖激酶-1中的ATP结合
Krishna Kant Vishwakarma1, Ullas Seetharam Kolthur2,3, Ravindra Venkatramani1
1Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Proteins
|July 16, 2024
概括
循环林依赖激酶1 (CDK1) 的乙化影响ATP结合和蛋白质相互作用. 分子动力学模拟揭示了CDK1活性位点及其蛋白质-蛋白质相互作用接口之间的全调节.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 循环素依赖激酶1 (CDK1) 对于细胞周期进展至关重要.
- CDK1的活性通过与Cyclin-B,基质和Cks蛋白的相互作用来调节.
- CDK1的活性位点乙化会影响循环林-B的结合,这表明远程通信.
研究的目的:
- 为了证明CDK1活性位点及其蛋白质-蛋白质相互作用 (PPI) 接口之间的性联系.
- 研究乙化对ATP与CDK1.1结合的作用.
- 阐明CDK1.1中远程通信的机制.
主要方法:
- 使用了原子分子动力学 (MD) 模拟.
- 计算了原生 (K33wt) 和修改的CDK1形式 (K33Ac,K33Q,K33R) 的ATP结合自由能量.
- 使用自由能量分解和统计分析来评估回应和相关性.
主要成果:
- 与改性形式相比,原生K33wt CDK1的ATP结合在K33wt CDK1中最强.
- 在ATP结合/扰动时,在α-螺旋,激活循环 (A-循环) 和β-β H段观察到非局部的热反应.
- 这些细分分别介导与Cyclin-B,基质和Cks蛋白相互作用.
- 在数据集的很大一部分中,输入性反应和动态变化之间的相关性丢失了.
结论:
- 在CDK1活性部位与其三个主要PPI接口之间存在一般的全性联系.
- 这项研究揭示了一种新的ATP结合调节模式,该调节方式由CDK1.1中的多个PPI接口介导.
- 活动部位和CDK1:Cyclin-B接口之间的双向通信得到确认.
相关概念视频
01:19Allosteric 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
01:08Allosteric Regulation
57.8K
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...
57.8K
02:39Positive Regulator Molecules
5.4K
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
5.4K
02:34Inhibition of Cdk Activity
4.7K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.7K
02:14GTPases and their Regulation
8.3K
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins,...
Large G-proteins,...
8.3K
01:58Cooperative Allosteric Transitions
2.3K
2.3K