Related Experiment Video

Updated: Jun 25, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

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

Crystal structure of human CDK4 in complex with a D-type cyclin

Philip J Day1, Anne Cleasby, Ian J Tickle

  • 1Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|February 25, 2009
PubMed

Insights

Researchers determined the crystal structure of the cyclin D1-cyclin-dependent kinase 4 (CDK4) complex. This structure reveals CDK4 in an inactive state, suggesting a unique regulatory mechanism for this key cell cycle protein.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex regulates cell cycle G1 phase progression.
  • Aberrant CDK4/cyclin D1 pathway regulation is implicated in multiple tumor types, making CDK4 a therapeutic target.
  • Determining the CDK4/cyclin D1 complex structure has been challenging.

Purpose of the Study:

  • To determine the crystal structure of the CDK4/cyclin D1 complex.
  • To elucidate the structural basis of CDK4 regulation and activation.

Main Methods:

  • X-ray crystallography
  • Structure determination at 2.3 A resolution

Main Results:

  • The crystal structure of CDK4 in complex with cyclin D1 was determined.
  • CDK4 was observed in an inactive conformation despite binding cyclin D1 and having a phosphorylated T-loop.
  • The heterodimer conformation differs from previously characterized CDK/cyclin complexes.

Conclusions:

  • The determined structure provides insights into a unique mechanism of CDK4 regulation and activation.
  • This structural information can inform the development of targeted therapies for cancers with aberrant CDK4/cyclin D1 pathway activity.

More Related Videos

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay12:26

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

Published on: May 3, 2018

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

Related Concept Videos

Positive Regulator Molecules02:39

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 Molecules01:45

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
M-Cdk Drives Transition Into Mitosis02:15

M-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...
M-Cdk Drives Transition Into Mitosis02:15

M-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...
Anaphase Promoting Complex00:50

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...
Inhibition of Cdk Activity02:34

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...