Crystal structure of human CDC7 kinase in complex with its activator DBF4

The kinase CDC7 is essential for replication initiation in eukaryote organisms. To exert its function, CDC7 requires its activator, DBF4. Now the crystal structures of a minimal CDC7–DBF4 complex, with bound nucleotide or inhibitor, along with functional analyses reveal that DBF4 wraps around CDC7,...

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Bibliographic Details
Published in:	Nature structural & molecular biology Vol. 19; no. 11; pp. 1101 - 1107
Main Authors:	Hughes, Siobhan, Elustondo, Frédéric, Di Fonzo, Andrea, Leroux, Frédéric G, Wong, Ai C, Snijders, Ambrosius P, Matthews, Stephen J, Cherepanov, Peter
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-11-2012 Nature Publishing Group
Subjects:	631/45/275 631/45/535 Amino Acid Sequence ATP Biochemistry Biological Microscopy Cell Cycle Proteins - chemistry Cell Cycle Proteins - metabolism Crystal structure Crystallization Deoxyribonucleic acid DNA DNA replication Humans Kinases Life Sciences Magnetic Resonance Spectroscopy Membrane Biology Models, Molecular Molecular biology Molecular Sequence Data Multiprotein Complexes - chemistry Multiprotein Complexes - metabolism Physiological aspects Protein Conformation Protein kinases Protein Structure Protein-Serine-Threonine Kinases - chemistry Protein-Serine-Threonine Kinases - metabolism Structure X-Ray Diffraction United Kingdom
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Summary:	The kinase CDC7 is essential for replication initiation in eukaryote organisms. To exert its function, CDC7 requires its activator, DBF4. Now the crystal structures of a minimal CDC7–DBF4 complex, with bound nucleotide or inhibitor, along with functional analyses reveal that DBF4 wraps around CDC7, stabilizing the αC helix in the N lobe and tethering the C lobe of the kinase. 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 Å 2 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 αC 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1545-9993 1545-9985
DOI:	10.1038/nsmb.2404