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Break CDK2/Cyclin E1 Interface Allosterically with Small Peptides

Author

Listed:
  • Hao Chen
  • Yunjie Zhao
  • Haotian Li
  • Dongyan Zhang
  • Yanzhao Huang
  • Qi Shen
  • Rachel Van Duyne
  • Fatah Kashanchi
  • Chen Zeng
  • Shiyong Liu

Abstract

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.

Suggested Citation

  • Hao Chen & Yunjie Zhao & Haotian Li & Dongyan Zhang & Yanzhao Huang & Qi Shen & Rachel Van Duyne & Fatah Kashanchi & Chen Zeng & Shiyong Liu, 2014. "Break CDK2/Cyclin E1 Interface Allosterically with Small Peptides," PLOS ONE, Public Library of Science, vol. 9(10), pages 1-11, October.
    • Handle: RePEc:plo:pone00:0109154
    DOI: 10.1371/journal.pone.0109154
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    2. Raphaël Bourgeas & Marie-Jeanne Basse & Xavier Morelli & Philippe Roche, 2010. "Atomic Analysis of Protein-Protein Interfaces with Known Inhibitors: The 2P2I Database," PLOS ONE, Public Library of Science, vol. 5(3), pages 1-11, March.
    3. James A. Wells & Christopher L. McClendon, 2007. "Reaching for high-hanging fruit in drug discovery at protein–protein interfaces," Nature, Nature, vol. 450(7172), pages 1001-1009, December.
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