5hq0

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Ternary complex of human proteins CDK1, Cyclin B and CKS2, bound to an inhibitor

Structural highlights

5hq0 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:LZ9
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CDK1_HUMAN Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins. Required in higher cells for entry into S-phase and mitosis. Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SIRT2 and RUNX2. CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs. Essential for early stages of embryonic development. During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation. Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis. Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation upon DNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair. Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C-mediated dephosphorylation and restoring cell cycle progression. In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons. The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis. NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis. The phosphorylation of Bcl-xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis. In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

Publication Abstract from PubMed

CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. Here we report the crystal structures of complexes of CDK1-Cks1 and CDK1-cyclin B-Cks2. These structures confirm the conserved nature of the inactive monomeric CDK fold and its ability to be remodelled by cyclin binding. Relative to CDK2-cyclin A, CDK1-cyclin B is less thermally stable, has a smaller interfacial surface, is more susceptible to activation segment dephosphorylation and shows differences in the substrate sequence features that determine activity. Both CDK1 and CDK2 are potential cancer targets for which selective compounds are required. We also describe the first structure of CDK1 bound to a potent ATP-competitive inhibitor and identify aspects of CDK1 structure and plasticity that might be exploited to develop CDK1-selective inhibitors.

CDK1 structures reveal conserved and unique features of the essential cell cycle CDK.,Brown NR, Korolchuk S, Martin MP, Stanley WA, Moukhametzianov R, Noble ME, Endicott JA Nat Commun. 2015 Apr 13;6:6769. doi: 10.1038/ncomms7769. PMID:25864384[15]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
11 reviews cite this structure
Structural insights into the functional diversity of the CDK-cyclin family.
Wood et al. (2018)
10 more
59 other articles
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See Also

References

  1. ↑ Fourest-Lieuvin A, Peris L, Gache V, Garcia-Saez I, Juillan-Binard C, Lantez V, Job D. Microtubule regulation in mitosis: tubulin phosphorylation by the cyclin-dependent kinase Cdk1. Mol Biol Cell. 2006 Mar;17(3):1041-50. Epub 2005 Dec 21. PMID:16371510 doi:http://dx.doi.org/10.1091/mbc.E05-07-0621
  2. ↑ Qiao M, Shapiro P, Fosbrink M, Rus H, Kumar R, Passaniti A. Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation. J Biol Chem. 2006 Mar 17;281(11):7118-28. Epub 2006 Jan 9. PMID:16407259 doi:http://dx.doi.org/10.1074/jbc.M508162200
  3. ↑ Southwood CM, Peppi M, Dryden S, Tainsky MA, Gow A. Microtubule deacetylases, SirT2 and HDAC6, in the nervous system. Neurochem Res. 2007 Feb;32(2):187-95. Epub 2006 Aug 25. PMID:16933150 doi:http://dx.doi.org/10.1007/s11064-006-9127-6
  4. ↑ Hu X, Cui D, Moscinski LC, Zhang X, Maccachero V, Zuckerman KS. TGFbeta regulates the expression and activities of G2 checkpoint kinases in human myeloid leukemia cells. Cytokine. 2007 Feb;37(2):155-62. Epub 2007 Apr 24. PMID:17459720 doi:http://dx.doi.org/10.1016/j.cyto.2007.03.009
  5. ↑ Yuan Z, Becker EB, Merlo P, Yamada T, DiBacco S, Konishi Y, Schaefer EM, Bonni A. Activation of FOXO1 by Cdk1 in cycling cells and postmitotic neurons. Science. 2008 Mar 21;319(5870):1665-8. doi: 10.1126/science.1152337. PMID:18356527 doi:10.1126/science.1152337
  6. ↑ Pomerening JR, Ubersax JA, Ferrell JE Jr. Rapid cycling and precocious termination of G1 phase in cells expressing CDK1AF. Mol Biol Cell. 2008 Aug;19(8):3426-41. doi: 10.1091/mbc.E08-02-0172. Epub 2008, May 14. PMID:18480403 doi:http://dx.doi.org/10.1091/mbc.E08-02-0172
  7. ↑ Zhang X, Chen Q, Feng J, Hou J, Yang F, Liu J, Jiang Q, Zhang C. Sequential phosphorylation of Nedd1 by Cdk1 and Plk1 is required for targeting of the gammaTuRC to the centrosome. J Cell Sci. 2009 Jul 1;122(Pt 13):2240-51. doi: 10.1242/jcs.042747. Epub 2009 Jun, 9. PMID:19509060 doi:10.1242/jcs.042747
  8. ↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
  9. ↑ Nakamura A, Naito M, Arai H, Fujita N. Mitotic phosphorylation of Aki1 at Ser208 by cyclin B1-Cdk1 complex. Biochem Biophys Res Commun. 2010 Mar 19;393(4):872-6. doi:, 10.1016/j.bbrc.2010.02.103. Epub 2010 Feb 18. PMID:20171170 doi:http://dx.doi.org/10.1016/j.bbrc.2010.02.103
  10. ↑ Timofeev O, Cizmecioglu O, Settele F, Kempf T, Hoffmann I. Cdc25 phosphatases are required for timely assembly of CDK1-cyclin B at the G2/M transition. J Biol Chem. 2010 May 28;285(22):16978-90. doi: 10.1074/jbc.M109.096552. Epub, 2010 Apr 1. PMID:20360007 doi:http://dx.doi.org/10.1074/jbc.M109.096552
  11. ↑ Yoon CH, Miah MA, Kim KP, Bae YS. New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses. EMBO Rep. 2010 May;11(5):393-9. doi: 10.1038/embor.2010.45. Epub 2010 Apr 16. PMID:20395957 doi:http://dx.doi.org/10.1038/embor.2010.45
  12. ↑ Chen S, Bohrer LR, Rai AN, Pan Y, Gan L, Zhou X, Bagchi A, Simon JA, Huang H. Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol. 2010 Nov;12(11):1108-14. doi: 10.1038/ncb2116. Epub 2010 Oct 10. PMID:20935635 doi:10.1038/ncb2116
  13. ↑ Matthess Y, Raab M, Sanhaji M, Lavrik IN, Strebhardt K. Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-8 activity. Mol Cell Biol. 2010 Dec;30(24):5726-40. doi: 10.1128/MCB.00731-10. Epub 2010 Oct , 11. PMID:20937773 doi:http://dx.doi.org/10.1128/MCB.00731-10
  14. ↑ Itoh G, Kanno S, Uchida KS, Chiba S, Sugino S, Watanabe K, Mizuno K, Yasui A, Hirota T, Tanaka K. CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment. EMBO J. 2011 Jan 5;30(1):130-44. doi: 10.1038/emboj.2010.276. Epub 2010 Nov 9. PMID:21063390 doi:http://dx.doi.org/10.1038/emboj.2010.276
  15. ↑ Brown NR, Korolchuk S, Martin MP, Stanley WA, Moukhametzianov R, Noble ME, Endicott JA. CDK1 structures reveal conserved and unique features of the essential cell cycle CDK. Nat Commun. 2015 Apr 13;6:6769. doi: 10.1038/ncomms7769. PMID:25864384 doi:http://dx.doi.org/10.1038/ncomms7769

Contents


PDB ID 5hq0

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