Members of the cyclin dependent protein kinase (CDK) family control both cell proliferation and gene transcription. Consequently, CDK-cyclin containing complexes are important in normal cells and their dysregulation underlies disease conditions, where theyrepresent proven actionable targets. In different cellular settings, each CDK-cyclin module is incorporated into protein assemblies of diverse composition that govern cell-type specific activities. Greater mechanistic understanding of the shared and unique interactions of CDK-cyclin complexes is required to explain their distinct roles and permit for selective inhibition for therapeutic purposes. FragLites are a crystallographic screening library that we have developed that both sensitively identifies interaction hotspots on a protein surface and provides leads for subsequent chemical probe discovery. We have already applied FragLite screening to several cyclins and different binding profiles can be distinguished.In this talk, the structures of various CDK-cyclin complexes will be presented and compared to FragLite maps to consider approaches that can be taken to identify sites that regulate CDK-cyclin activity and to assess their tractability to targeting with chemical probes.
Professor Jane Endicott received her PhD from the University of Toronto working with Professor Victor Ling on the characterisation of P-glycoproteins and mechanisms of multidrug resistance. She then moved to the University of Oxford as a Junior Research Fellow of the National Cancer Institute of Canada to work with Professor Dame Louise Johnson and Professor Sir Paul Nurse on the structural characterisation of proteins that control the eukaryotic cell cycle. She stayed in Oxford to continue this work first as a Royal Society University Research Fellow and thenas a Lecturer in the Department of Biochemistry. She relocatedto Newcastle University in 2011 to join the CRUK Drug DiscoveryGroupwhere she is currently the Professor of Cancer Structural Biology. Hergroup takes a structure-lead multidisciplinary approachto understandthe mechanisms by which cyclindependent proteinkinase (CDK)-containing complexes regulate the eukaryotic cell cycleand transcription. Aberrant CDK activity has been linked to cancer, neurological diseases,and rheumatoid arthritis, and CDK-selective ATP-competitive inhibitorsare in clinical trials for the treatment of cancer. However, structural studies have revealed other small molecule binding sites on CDK-cyclincomplexes that may provide alternative targets for CDK-directed therapies. Her group aims to characterise the CDK and cyclin families to improve our understanding of the functions of this important enzymeclass, their regulation and to aid the further development of CDKinhibitors. She is a member of the Biochemical Society, was elected as a Fellow of the Royal Society of Biology in 2012 and awarded an MRC Suffrage Science Award in 2014.
