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The Structural and Functional Characterisation of Human Cdc7 Kinase

Dick, SD; (2017) The Structural and Functional Characterisation of Human Cdc7 Kinase. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Cell division cycle 7-related Ser/Thr (Cdc7) kinase is conserved and essential across eukaryotes. When bound to its activator, dumbbell-forming factor 4 (Dbf4) it phosphorylates a number of target proteins involved in various aspects of the cell cycle, including replication initiation, meiosis, the intra S-phase checkpoint, the DNA damage response and mitotic exit. Cdc7 is overexpressed in a number of cancers and expression correlates with patient prognosis. Selective inhibition of Cdc7 leads to cell death through an aberrant S-phase in transformed cells, while healthy fibroblasts are able to survive such treatments. Therefore, Cdc7 is an attractive target for cancer therapeutics, and high-resolution structural information could be very informative for the development of small molecule inhibitors. Herein, I present crystal structures of a fully active Cdc7-Dbf4 heterodimeric construct bound to a potent Cdc7 inhibitor, a non-hydrolysable ATP analogue and an Mcm2-derived substrate peptide. These structures, refined to a high resolution, reveal a previously unseen Zn-binding domain that supports a fully open conformation of the active site. The structures also reveal features required for substrate binding and phosphorylation. In vitro assays have been employed to validate the functional significance of these features, and an in cellula system developed to investigate their importance in the cell. The new structural and functional information gained from this study will inform the design of small molecule inhibitors of Cdc7 while the cell-based system opens up new ways of addressing the functions of the unique kinase insert sequences of Cdc7.

Type: Thesis (Doctoral)
Title: The Structural and Functional Characterisation of Human Cdc7 Kinase
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1537309
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