title: Break CDK2/Cyclin E1 interface allosterically with small peptides.
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.
authors.affiliation: Department of Physics, The George Washington University, Washington, D. C., United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Physics, The George Washington University, Washington, D. C., United States of America.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Haotian
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Yanzhao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: BNLMS, Center for Quantitative Biology, Peking University, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Rachel
authors.initials: R
authors.lastname: Van Duyne
authors.affiliation: George Mason University, National Center for Biodefense & Infectious Diseases, Manassas, Virginia, United States of America.
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
authors.affiliation: 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Liu
mesh_terms: D000494:Allosteric Regulation; D019927:Cyclin E / Q000737:chemistry* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015513:Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D020349:Surface Plasmon Resonance
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D010455:Peptides; D051357:Cyclin-Dependent Kinase 2