在Cdc4β螺旋的叶片上使用化Cdk抑制剂
1Programs in Chemical Biology and Cancer Biology and Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Cell
|January 30, 2003
概括
酸化调节了SCF-Cdc4泛基因化酶的基质结合. 一个新的晶体结构揭示了Cdc4如何与酸化基质结合,解释了单个位点的调节机制.
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:
- 该SCF-Cdc4泛基因酶复合体在细胞循环调节和蛋白质降解中发挥着关键作用.
- 已知酸化事件调节SCF-Cdc4.4的活性和基质特异性.
- 了解基质识别的精确分子机制对于破译细胞信号通路至关重要.
研究的目的:
- 阐明SCF-Cdc4泛基酶的Cdc4亚单元对基质的结合的结构基础.
- 研究酸化如何调节Cdc4及其高亲和基质之间的相互作用.
- 提供关于多个调节性酸化在单个结合部位协调的机制的见解.
主要方法:
- 使用X射线结晶学来确定Cdc4亚单元的结构.
- Cdc4在复合体中结晶,并与高亲和度基质聚酸结晶.
- 进行结构分析以描述绑定界面和相互作用.
主要成果:
- 确定了Cdc4与高亲和力基质结合的晶体结构.
- 获得了关于Cdc4和化基质之间的特定结合相互作用的详细见解.
- 这些发现表明,单个结合部位如何适应并受到多个酸化事件的调节的机制.
结论:
- 确定的结构为SCF-Cdc4如何识别酸化基质提供了分子理解.
- 这项工作揭示了通过酸化调节无素酶活性的精确机制.
- 这些发现对了解细胞循环控制和蛋白质循环途径有意义.
相关概念视频
01:45Positive Regulator Molecules
To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
02:39Positive Regulator Molecules
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.
02:34Inhibition of Cdk Activity
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...
02:15M-Cdk Drives Transition Into Mitosis
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
00:50Anaphase Promoting Complex
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
02:34Inhibition of CDK Activity
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...