Break CDK2/Cyclin E1 interface allosterically with small peptides

PLoS One. 2014 Oct 7;9(10):e109154. doi: 10.1371/journal.pone.0109154. eCollection 2014.


Most inhibitors of Cyclin-dependent kinase 2 (CDK2) target its ATP-binding pocket. It is difficult, however, to use this pocket to design very specific inhibitors because this catalytic pocket is highly conserved in the protein family of CDKs. Here we report some short peptides targeting a noncatalytic pocket near the interface of the CDK2/Cyclin complex. Docking and molecular dynamics simulations were used to select the peptides, and detailed dynamical network analysis revealed that these peptides weaken the complex formation via allosteric interactions. Our experiments showed that upon binding to the noncatalytic pocket, these peptides break the CDK2/Cyclin complex partially and diminish its kinase activity in vitro. The binding affinity of these peptides measured by Surface Plasmon Resonance can reach as low as 0.5 µM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Cyclin E / chemistry*
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / chemistry*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Oncogene Proteins / chemistry*
  • Oncogene Proteins / metabolism
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Surface Plasmon Resonance


  • CCNE1 protein, human
  • Cyclin E
  • Oncogene Proteins
  • Peptides
  • Cyclin-Dependent Kinase 2