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

Break CDK2/Cyclin E1 interface allosterically with small peptides.

Author information

1
Department of Physics, The George Washington University, Washington, D. C., United States of America.
2
Department of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China.
3
BNLMS, Center for Quantitative Biology, Peking University, Beijing, China.
4
George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, Virginia, United States of America; The George Washington University Medical Center, Department of Microbiology, Immunology, and Tropical Medicine, Washington, D. C., United States of America.
5
George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, Virginia, United States of America.
6
Department of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Physics, The George Washington University, Washington, D. C., United States of America.

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.

PMID:
25290691
PMCID:
PMC4188581
DOI:
10.1371/journal.pone.0109154
[Indexed for MEDLINE]
Free PMC Article

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