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Crystal structure of human CDC7 kinase in complex with its activator DBF4.

Hughes S, Elustondo F, Di Fonzo A, Leroux FG, Wong AC, Snijders AP, Matthews SJ, Cherepanov P
Nat Struct Mol Biol 19 1101-7 (2012)
Related entries: 4f99, 4f9b, 4f9c

Cited: 44 times
EuropePMC logo PMID: 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.

Articles - 4f9a mentioned but not cited (3)

  1. Evolution of protein kinase substrate recognition at the active site. Bradley D, Beltrao P. PLoS Biol 17 e3000341 (2019)
  2. p53 controls CDC7 levels to reinforce G1 cell cycle arrest upon genotoxic stress. Tudzarova S, Mulholland P, Dey A, Stoeber K, Okorokov AL, Williams GH. Cell Cycle 15 2958-2972 (2016)
  3. Druggable cavities and allosteric modulators of the cell division cycle 7 (CDC7) kinase. Rojas-Prats E, Martinez-Gonzalez L, Gil C, Ramírez D, Martinez A, Martinez A. J Enzyme Inhib Med Chem 39 2301767 (2024)


Reviews citing this publication (2)

  1. Structural simplification: an efficient strategy in lead optimization. Wang S, Dong G, Sheng C. Acta Pharm Sin B 9 880-901 (2019)
  2. Dbf4: the whole is greater than the sum of its parts. Matthews LA, Guarné A. Cell Cycle 12 1180-1188 (2013)

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  17. Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors. Reichelt A, Bailis JM, Bartberger MD, Yao G, Shu H, Kaller MR, Allen JG, Weidner MF, Keegan KS, Dao JH. Eur J Med Chem 80 364-382 (2014)
  18. The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer. Saleh A, Noguchi Y, Aramayo R, Ivanova ME, Stevens KM, Montoya A, Sunidhi S, Carranza NL, Skwark MJ, Speck C. Nat Commun 13 2915 (2022)
  19. Characterization of a Drosophila ortholog of the Cdc7 kinase: a role for Cdc7 in endoreplication independent of Chiffon. Stephenson R, Hosler MR, Gavande NS, Ghosh AK, Weake VM. J Biol Chem 290 1332-1347 (2015)
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  26. 2-Aminomethylthieno[3,2-d]pyrimidin-4(3H)-ones bearing 3-methylpyrazole hinge binding moiety: Highly potent, selective, and time-dependent inhibitors of Cdc7 kinase. Kurasawa O, Homma M, Oguro Y, Miyazaki T, Mori K, Uchiyama N, Iwai K, Ohashi A, Hara H, Yoshida S, Cho N. Bioorg Med Chem 25 3658-3670 (2017)
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  28. Identification of a new class of potent Cdc7 inhibitors designed by putative pharmacophore model: Synthesis and biological evaluation of 2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-ones. Kurasawa O, Oguro Y, Miyazaki T, Homma M, Mori K, Iwai K, Hara H, Skene R, Hoffman I, Ohashi A, Yoshida S, Ishikawa T, Cho N. Bioorg Med Chem 25 2133-2147 (2017)
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  34. Conformational Properties and Putative Bioactive Targets for Novel Thiosemicarbazone Derivatives. Georgiou N, Cheilari A, Karta D, Chontzopoulou E, Plavec J, Tzeli D, Vassiliou S, Mavromoustakos T. Molecules 27 4548 (2022)
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