An Inhibitor’s-Eye View of the ATP-Binding Site of CDKs in Different Regulatory States

Aude Echalier,Jane A Endicott,Alison J Hole,Graziano Lolli,Martin E M Noble

doi:10.1021/cb500135f

Aude Echalier, Jane A Endicott + Show 3 more

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Journal: ACS Chemical Biology	Publication Date: Apr 10, 2014
Citations: 28	License type: cc-by

Affiliation: University of Oxford, University of Padua

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We have used a chemically diverse panel of kinase inhibitors to assess the chemical similarity of the ATP-binding sites of cyclin-dependent kinase (CDK) subfamily members in a range of activation states. Using this approach, we find that different activation states of a particular CDK may differ from each other as much as different CDKs in the same activation state. We also find that inhibitors discriminate more effectively among CDK family members in their monomeric state than in their cyclin-bound state, providing direct evidence for the belief that selective binding to inactive kinase states might be more readily achieved than selective binding to active states.

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The eukaryotic serine/threonine and tyrosine protein kinase family is characterized by a conserved fold in which residues from both the N- and C-terminal lobes contribute to the active site.[7,8] The identities of the residues that line the ATP binding pocket and the structural plasticity of the protein kinase fold constitute two key elements that together determine the inhibitor-binding profile of a protein kinase
CDK2 was prepared in four different conformational states: monomeric unphosphorylated (CDK2), monomeric phosphorylated on Thr[160], unphosphorylated in complex with human cyclin A175−432 (CDK2/A), and Thr160phosphorylated in complex with human cyclin A175−432
CDK4 was characterized both as an inactive, nonphosphorylated monomer (CDK4) and as the fully activated binary complex (CDK4/cyclin D3 phosphorylated on Thr[172], pCDK4/D)

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Introduction

The eukaryotic serine/threonine and tyrosine protein kinase family is characterized by a conserved fold in which residues from both the N- and C-terminal lobes contribute to the active site.[7,8] The identities of the residues that line the ATP binding pocket and the structural plasticity of the protein kinase fold constitute two key elements that together determine the inhibitor-binding profile of a protein kinase. (c) Comparison of CDK2 inhibitor fingerprints in different activation states.

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