Related Experiment Video

Updated: Jul 16, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic

Markus A Seeliger1, Bhushan Nagar, Filipp Frank

  • 1Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA.

Structure (London, England : 1993)
|March 16, 2007
PubMed

Insights

Imatinib, a cancer drug, is less effective against c-Src kinase than expected. Destabilizing inactive states of c-Src kinase significantly increases imatinib sensitivity, revealing key binding mechanisms.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Imatinib is a tyrosine kinase inhibitor targeting c-Abl, c-Kit, and PDGF receptor.
  • Imatinib exhibits reduced efficacy against c-Src kinase, despite conserved imatinib-binding residues in Abl and c-Kit.

Purpose of the Study:

  • To investigate the molecular basis for imatinib's differential efficacy against c-Src kinase.
  • To understand the structural and thermodynamic factors governing imatinib binding to c-Src.

Main Methods:

  • Comparative analysis of crystal structures of imatinib-bound kinases (Abl, c-Kit, c-Src).
  • Site-directed mutagenesis to swap residues between c-Src and c-Abl.
  • Assessing drug sensitivity following mutations destabilizing the inactive Src/CDK conformation.

Main Results:

  • The crystal structure of c-Src*imatinib resembles active Abl*imatinib and c-Kit*imatinib, differing from the inactive Src/CDK conformation.
  • Residue swapping between c-Src and c-Abl did not enhance imatinib affinity, indicating distributed thermodynamic penalties.
  • Mutations destabilizing the inactive Src/CDK conformation increased imatinib sensitivity 15-fold.

Conclusions:

  • The binding of imatinib to c-Src is influenced by the energetic balance between distinct inactive conformations.
  • Understanding these conformational dynamics is crucial for optimizing imatinib efficacy and developing new kinase inhibitors.

More Related Videos

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

Related Concept Videos

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...
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...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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...