Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase.

Structure
Samual D DickPeter Cherepanov

Abstract

CDC7 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.

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Citations

Feb 14, 2021·Drug Discovery Today·Christian Bailly, Gérard Vergoten
Feb 13, 2021·Biochemical Pharmacology·Christian Bailly

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Methods Mentioned

BETA
co-crystallization
size exclusion chromatography
X-Ray

Software Mentioned

PyMOL
Phenix Autobuild
Excel
XDS
Refmac
Phenix refine
Coot
Scala
Clashscore
Xia2

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