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- Title
Crystal structure of human CDC7 kinase in complex with its activator DBF4.
- Authors
Hughes, Siobhan; Elustondo, Frédéric; Di Fonzo, Andrea; Leroux, Frédéric G; Wong, Ai C; Snijders, Ambrosius P; Matthews, Stephen J; Cherepanov, Peter
- Abstract
CDC7 is a serine/threonine kinase that is essential for the initiation of eukaryotic DNA replication. CDC7 activity is controlled by its activator, DBF4. Here we present crystal structures of human CDC7-DBF4 in complex with a nucleotide or ATP-competing small molecules, revealing the active and inhibited forms of the kinase, respectively. DBF4 wraps around CDC7, burying approximately 6,000 Å2 of hydrophobic molecular surface in a bipartite interface. The effector domain of DBF4, containing conserved motif C, is essential and sufficient to support CDC7 kinase activity by binding to the kinase N-terminal lobe and stabilizing its canonical ?C helix. DBF4 motif M latches onto the C-terminal lobe of the kinase, acting as a tethering domain. Our results elucidate the structural basis for binding to and activation of CDC7 by DBF4 and provide a framework for the design of more potent and specific CDC7 inhibitors.
- Subjects
SERINE/THREONINE kinases; DNA replication; ADENOSINE triphosphate; BIPARTITE graphs; CYCLIN-dependent kinases; CANCER cell physiology
- Publication
Nature Structural & Molecular Biology, 2012, Vol 19, Issue 11, p1101
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.2404