PDBsum entry 4f99

Transferase

PDB id: 4f99

Contents

Protein chains

312 a.a.

90 a.a.

Ligands

ADP

Metals

_MG

_ZN

Waters ×48

References listed in PDB file

Key reference

• Title: Crystal structure of human cdc7 kinase in complex with its activator dbf4.
• Authors: S.Hughes, F.Elustondo, A.Di fonzo, F.G.Leroux, A.C.Wong, A.P.Snijders, S.J.Matthews, P.Cherepanov.
• Ref.: Nat Struct Biol, 2012, 19, 1101-1107.
• PubMed id: 23064647

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 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.