Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/4179
Title: Structural and functional characterisation of cyclin dependent kinase 1 containing complexes
Authors: Korolchuk, Svitlana Mykolaivna
Issue Date: 2018
Publisher: Newcastle University
Abstract: CDK1 belongs to the family of serine/threonine kinases that require cyclin binding and phosphorylation for activation. CDK1 is partnered by cyclin A or cyclin B and is the only essential CDK that is required to drive the eukaryotic cell cycle. Because of their roles in driving cell growth and division, the activities of some members of the CDK family are upregulated in different cancer types making them attractive targets for therapy. The structure of monomeric CDK1 bound to CKS1 and in a complex with cyclin B are presented. These structures confirm the conserved inactive monomeric CDK fold and show how it can be remodelled by cyclin binding. These structures have revealed important insights for our understanding of CDK function and regulation as well as for the development of new more potent and specific drugs. A range of biophysical and biochemical techniques have been used to confirm and develop hypotheses as to the regulation and activity of CDK1 proposed by the structures. The melting temperature of CDK1 was estimated and compared to that of the cyclin B bound complex, CDK2 and CDK2-cyclin A to determine if the smaller interface between CDK1 and cyclin B may have implications for protein stability. The CDK1–cyclin B structures also reveal potential novel protein interaction sites that might regulate CDK1 activity. These findings inspired further investigations to explore binding sites by structural biology methods. CDK1 can phosphorylate the largest number of substrates in comparison to other CDKs. This relaxed substrate specificity was explored with reference to the insights provided by the CDK1-cyclin B-CKS2 structure. The similarities in sequence and secondary structure exhibited by the CDK family pose challenges for inhibitor design. The binding modes of a diverse set of inhibitors were characterized by a range of biophysical methods and their structures were determined by X-ray crystallography. The results of these experiments highlight the importance of conformational plasticity of the whole molecule in shaping the ATP binding site.
Description: PhD Thesis
URI: http://hdl.handle.net/10443/4179
Appears in Collections:Northern Institute for Cancer Research

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