The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases

  title={The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases},
  author={Nick R. Brown and Martin E. M. Noble and Jane A. Endicott and Louise N. Johnson},
  journal={Nature Cell Biology},
Progression through the eukaryotic cell cycle is driven by the orderly activation of cyclin-dependent kinases (CDKs). For activity, CDKs require association with a cyclin and phosphorylation by a separate protein kinase at a conserved threonine residue (T160 in CDK2). Here we present the structure of a complex consisting of phosphorylated CDK2 and cyclin A together with an optimal peptide substrate, HHASPRK. This structure provides an explanation for the specificity of CDK2 towards the proline… 
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The role of Thr160 phosphorylation of Cdk2 in substrate recognition.
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Identification of substrates for cyclin dependent kinases.
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Role of phosphorylated Thr160 for the activation of the CDK2/Cyclin A complex
A comparative molecular dynamics study of models of the complex CDK2/Cyclin A/Substrate, which differ for the presence or absence of the phosphate group bound to Thr160, points to a decreased flexibility of the AL in the phosphorylated model, in fairly good agreement with experimental data.
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A novel computational procedure to predict substrates of the cyclin-dependent kinase Cdc28 (Cdk1) in the Saccharomyces cerevisiae by defining the local sequence motifs that represent the CDC28 phosphorylation sites and subsequently model clustering of these motifs within the protein sequences.


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A mechanism by which cyclins can recruit substrates to cdks is defined, and the results support the notion that a high local concentration of substrate provided by a protein-protein interaction distant from the active site is critical for phosphorylation by cdks.
Structural basis of cyclin-dependent kinase activation by phosphorylation
Comparison with the unphosphorylated CDK2–CyclinA complex shows that the T-loop moves by as much as 7 Å, and this affects the putative substrate binding site as well as resulting in additional CDK 2–Cy ClinA contacts.
Differences in substrate specificity between Cdk2-cyclin A and Cdk2-cyclin E in vitro.
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The crystal structure of cyclin A.
Identification of Substrate Binding Site of Cyclin-dependent Kinase 5*
The experimental data and computer simulations suggest that Asp86 and Asp91 are key residues that interact with the lysines at positions n+2 and/or n+3 of the substrates.
A Predictive Scale for Evaluating Cyclin-dependent Kinase Substrates
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Effects of Phosphorylation of Threonine 160 on Cyclin-dependent Kinase 2 Structure and Activity*
Phosphorylated cyclin-dependent protein kinase 2 (CDK2) is prepared for crystallization using the CDK-activating kinase 1 (CAK1) from Saccharomyces cerevisiae and grown crystals using microseeding techniques.
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The crystal structure of the human p27Kip1 kinase inhibitory domain bound to the phosphorylated cyclin A–cyclin-dependent kinase 2 (Cdk2) complex has been determined at 2.3 Å. p27Kip1 binds the