Break CDK2/Cyclin E1 interface allosterically with small peptides

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

doi:10.1371/journal.pone.0109154

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Break CDK2/Cyclin E1 interface allosterically with small peptides

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Break CDK2/Cyclin E1 interface allosterically with small peptides

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

PloS one, v 9(10), e109154

07 Oct 2014

DOI: https://doi.org/10.1371/journal.pone.0109154

PMID: 25290691

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Abstract

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

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.

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Title: Break CDK2/Cyclin E1 interface allosterically with small peptides
Creators: Hao Chen - George Washington University
Yunjie Zhao - George Washington University
Haotian Li - Huazhong University of Science and Technology
Dongyan Zhang - Huazhong University of Science and Technology
Yanzhao Huang - Huazhong University of Science and Technology
Qi Shen - Peking University
Rachel Van Duyne - George Mason University
Fatah Kashanchi - George Mason University
Chen Zeng - Huazhong University of Science and Technology
Shiyong Liu - Huazhong University of Science and Technology
Publication Details: PloS one, v 9(10), e109154
Publisher: Public LIbrary of Science (PLOS)
Grant note: R01 AI043894 / NIAID NIH HHS AI043894 / NIAID NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Pharmacology and Physiology
Web of Science ID: WOS:000342798000040
Scopus ID: 2-s2.0-84907854986
Other Identifier: 991021902523004721

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Collaboration types: Domestic collaboration; International collaboration
Web of Science research areas: Biochemistry & Molecular Biology

Break CDK2/Cyclin E1 interface allosterically with small peptides

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UN Sustainable Development Goals (SDGs)

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