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Inhibition of Cdk Activity

Inhibition 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...

Inhibition of CDK Activity

Inhibition of CDK Activity

Positive Regulator Molecules

Positive 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.

Positive Regulator Molecules

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.

Anaphase Promoting Complex

Anaphase 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...

Separation of Sister Chromatids

Separation of Sister Chromatids

At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...

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Related Experiment Video

Updated: Apr 22, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Break CDK2/Cyclin E1 interface allosterically with small peptides.

Hao Chen¹, Yunjie Zhao¹, Haotian Li²

¹Department of Physics, The George Washington University, Washington, D. C., United States of America.

|October 8, 2014

Summary

This summary is machine-generated.

Researchers developed novel peptides targeting a unique pocket in Cyclin-dependent kinase 2 (CDK2) to inhibit its activity. These peptides allosterically disrupt the CDK2/Cyclin complex, offering a new strategy for specific kinase inhibition.

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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

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Peptide-based Identification of Functional Motifs and their Binding Partners

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Related Experiment Videos

Last Updated: Apr 22, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

Peptide-based Identification of Functional Motifs and their Binding Partners

Peptide-based Identification of Functional Motifs and their Binding Partners

Published on: June 30, 2013

Area of Science:

Biochemistry
Molecular Biology
Drug Discovery

Background:

Cyclin-dependent kinase 2 (CDK2) is a key regulator of the cell cycle.
Targeting the conserved ATP-binding pocket of CDK2 for inhibitors is challenging due to lack of specificity.
Novel strategies are needed to develop specific CDK2 inhibitors.

Purpose of the Study:

To identify and characterize novel peptide inhibitors targeting a noncatalytic pocket of CDK2.
To investigate the mechanism of inhibition by these peptides.
To evaluate the efficacy of these peptides in disrupting the CDK2/Cyclin complex and kinase activity.

Main Methods:

Computational methods including molecular docking and molecular dynamics simulations were employed for peptide selection.
Dynamical network analysis was used to understand allosteric interactions.
In vitro experiments, including Surface Plasmon Resonance (SPR), were conducted to measure binding affinity and kinase activity.

Main Results:

Short peptides targeting a noncatalytic pocket near the CDK2/Cyclin interface were identified.
These peptides were shown to weaken the CDK2/Cyclin complex formation through allosteric interactions.
Peptide binding partially breaks the complex and diminishes CDK2 kinase activity in vitro.
High binding affinity, as low as 0.5 µM, was measured using SPR.

Conclusions:

Targeting noncatalytic pockets offers a promising strategy for developing specific CDK2 inhibitors.
Allosteric inhibition via peptides provides a novel approach to modulate kinase activity.
These findings open new avenues for therapeutic interventions in diseases involving CDK2 dysregulation.