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CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that has emerged as a key regulator of neurite outgrowth, vesicle trafficking and cancer cell proliferation. CDK16 is activated through binding to cyclin Y via a phosphorylation-dependent 14-3-3 interaction and has a unique consensus substrate phosphorylation motif compared with conventional CDKs. To elucidate the structure and inhibitor-binding properties of this atypical CDK, we screened the CDK16 kinase domain against different inhibitor libraries and determined the co-structures of identified hits. We discovered that the ATP-binding pocket of CDK16 can accommodate both type I and type II kinase inhibitors. The most potent CDK16 inhibitors revealed by cell-free and cell-based assays were the multitargeted cancer drugs dabrafenib and rebastinib. An inactive DFG-out binding conformation was confirmed by the first crystal structures of CDK16 in separate complexes with the inhibitors indirubin E804 and rebastinib, respectively. The structures revealed considerable conformational plasticity, suggesting that the isolated CDK16 kinase domain was relatively unstable in the absence of a cyclin partner. The unusual structural features and chemical scaffolds identified here hold promise for the development of more selective CDK16 inhibitors and provide opportunity to better characterise the role of CDK16 and its related CDK family members in various physiological and pathological contexts.

Original publication

DOI

10.1042/BCJ20160941

Type

Journal article

Journal

Biochem J

Publication Date

20/02/2017

Volume

474

Pages

699 - 713

Keywords

CCNY, PCTAIRE1, PCTK1, cyclin, kinase, phosphorylation, 14-3-3 Proteins, Adenosine Triphosphate, Amino Acid Sequence, Antineoplastic Agents, Binding Sites, Cloning, Molecular, Crystallography, X-Ray, Cyclin-Dependent Kinases, Cyclins, Escherichia coli, Gene Expression, Humans, Imidazoles, Indoles, Kinetics, Ligands, Oximes, Phosphorylation, Protein Binding, Protein Domains, Protein Kinase Inhibitors, Protein Structure, Secondary, Recombinant Proteins