6ya6
Minimal construct of Cdc7-Dbf4 bound to XL413Minimal construct of Cdc7-Dbf4 bound to XL413
Structural highlights
Function[CDC7_HUMAN] Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3.[1] [DBF4A_HUMAN] Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S phase. The complex CDC7-DBF4A selectively phosphorylates MCM2 subunit at 'Ser-40' and 'Ser-53' and then is involved in regulating the initiation of DNA replication during cell cycle.[2] [3] [4] Publication Abstract from PubMedCDC7 is an essential Ser/Thr kinase that acts upon the replicative helicase throughout the S phase of the cell cycle and is activated by DBF4. Here, we present crystal structures of a highly active human CDC7-DBF4 construct. The structures reveal a zinc-finger domain at the end of the kinase insert 2 that pins the CDC7 activation loop to motif M of DBF4 and the C lobe of CDC7. These interactions lead to ordering of the substrate-binding platform and full opening of the kinase active site. In a co-crystal structure with a mimic of MCM2 Ser40 phosphorylation target, the invariant CDC7 residues Arg373 and Arg380 engage phospho-Ser41 at substrate P+1 position, explaining the selectivity of the S-phase kinase for Ser/Thr residues followed by a pre-phosphorylated or an acidic residue. Our results clarify the role of DBF4 in activation of CDC7 and elucidate the structural basis for recognition of its preferred substrates. Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase.,Dick SD, Federico S, Hughes SM, Pye VE, O'Reilly N, Cherepanov P Structure. 2020 Jun 5. pii: S0969-2126(20)30179-9. doi:, 10.1016/j.str.2020.05.010. PMID:32521228[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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