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Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1
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Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1

Published on: February 25, 2016

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Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK

Daniel J Wood1, Svitlana Korolchuk1, Natalie J Tatum1

  • 1Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.

Cell Chemical Biology
|November 26, 2018
PubMed

Insights

Researchers explored cyclin-dependent kinase (CDK) inhibitors for cancer therapy. They found differences in cyclin-free CDK1 and CDK2 binding properties, suggesting new therapeutic strategies for targeting specific cancers.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Cell cycle dysregulation is a hallmark of many cancers, driving interest in cyclin-dependent kinase (CDK) inhibitors.
  • CDK2 inhibitors show promise for cancers with CCNE1 amplification, but off-target inhibition of CDK1 causes toxicity.

Purpose of the Study:

  • To investigate the binding properties of ATP-competitive inhibitors with cyclin-free and cyclin-bound CDK1 and CDK2.
  • To understand the basis for differential inhibitor binding between CDK1 and CDK2.

Main Methods:

  • Biophysical measurements
  • X-ray crystallography
  • Molecular dynamics simulations

Main Results:

  • Inhibitors can distinguish between cyclin-free CDK1 and CDK2, but not when they are cyclin-bound.
  • Differences in inhibitor binding correlate with contacts between the N- and C-lobes of the kinases.
  • A subtle but significant difference exists in the conformational energy landscapes of cyclin-free CDK1 and CDK2.

Conclusions:

  • The distinct conformational properties of cyclin-free CDK1 and CDK2 offer opportunities for developing selective kinase inhibitors.
  • Exploiting CDK1's unique characteristics could lead to improved cancer therapeutics with reduced toxicity.
Keywords:
CDKCDK1CDK2DSFITCSPRX-ray crystallographyactivity assaycell cyclecyclin-dependent kinasesdrug designinhibitor

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