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Structural basis for the activation and target site specificity of CDC7 kinaser

DOI: 10.1016/j.str.2020.05.010 DOI Help

Authors: Samual D. Dick (The Francis Crick Institute) , Stefania Federico (The Francis Crick Institute) , Siobhan M. Hughes (The Francis Crick Institute) , Valerie E. Pye (The Francis Crick Institute (Midland Road)) , Nicola O'Reilly (The Francis Crick Institute) , Peter Cherepanov (The Francis Crick Institute; Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: June 2020
Diamond Proposal Number(s): 9424

Open Access Open Access

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.

Journal Keywords: kinase; crystal structure; zinc-binding domain; cell cycle; DDK; CDC7; DBF4; XL413; bisubstrate; kinase inhibitor

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF

Documents:
1-s2.0-S0969212620301799-main.pdf

Discipline Tags:

Life Sciences & Biotech Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)