Crystal structure of human CDC7 kinase in complex with its activator DBF4.
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.
Cancer Research UK, London Research Institute, Clare Hall Laboratories, Potters Bar, UK.
Siobhan
S
Hughes
Frédéric
F
Elustondo
Andrea
A
Di Fonzo
Frédéric G
FG
Leroux
Ai C
AC
Wong
Ambrosius P
AP
Snijders
Stephen J
SJ
Matthews
Peter
P
Cherepanov
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D003460:Crystallization; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D014961:X-Ray Diffraction
D018797:Cell Cycle Proteins; C485678:DBF4 protein, human; D046912:Multiprotein Complexes; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases