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

DOI: 10.1038/nsmb.2404 DOI Help
PMID: 23064647 PMID Help

Authors: Siobhan Hughes (Cancer Research UK) , Frédéric Elustondo (Wolfson Institute for Biomedical Research) , Andrea Di Fonzo (Cancer Research UK) , Frédéric G. Leroux (Wolfson Institute for Biomedical Research) , Ai C. Wong (Wolfson Institute for Biomedical Research) , Ambrosius P. Snijders (Cancer Research UK) , Stephen J. Matthews (Imperial College London) , Peter Cherepanov (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 19 (11) , PAGES 1101 - 1107

State: Published (Approved)
Published: October 2012

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.

Journal Keywords: Cell; Crystallization; Humans; Magnetic; Models; Molecular; MultiProtein; Protein-Serine-Threonine; X-Ray Diffraction

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 08/01/2013 16:30

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