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Structure and inhibitor specificity of the PCTAIRE-family kinase CDK16

DOI: 10.1042/BCJ20160941 DOI Help

Authors: Sarah E. Dixon-Clarke (University of Oxford) , Saifeldin N Shehata (Nestle Institute of Health Sciences SA) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Timothy D. Sharpe (University of Oxford; University of Basel) , Frank Von Delft (Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford; Diamond Light Source; Department of Biochemistry, University of Johannesburg) , Kei Sakamoto (Nestle Institute of Health Sciences SA) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Biochemical Journal

State: Published (Approved)
Published: January 2017
Diamond Proposal Number(s): 10619 , 442

Open Access Open Access

Abstract: CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent protein 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 an unique consensus substrate phosphorylation motif compared to 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 multi-targeted 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.

Journal Keywords: PCTAIRE1; PCTK1; kinase; CCNY; cyclin; phosphorylation

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 02/02/2017 12:28


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)