6gu4

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CDK1/CyclinB/Cks2 in complex with CGP74514A

Structural highlights

6gu4 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:FC8
Gene:CDK1, CDC2, CDC28A, CDKN1, P34CDC2 (HUMAN), CCNB1, CCNB (HUMAN), CKS2 (HUMAN)
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] [CKS2_HUMAN] Binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function. [CCNB1_HUMAN] Essential for the control of the cell cycle at the G2/M (mitosis) transition.[15] [16]

Publication Abstract from PubMed

Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.

Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition.,Wood DJ, Korolchuk S, Tatum NJ, Wang LZ, Endicott JA, Noble MEM, Martin MP Cell Chem Biol. 2018 Nov 1. pii: S2451-9456(18)30375-1. doi:, 10.1016/j.chembiol.2018.10.015. PMID:30472117[17]

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

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Citations
2 reviews cite this structure
Cell cycle on the crossroad of tumorigenesis and cancer therapy.
Liu et al. (2022)
1 more
26 other articles
No citations found

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, Lowe ED, Petri E, Skamnaki V, Antrobus R, Johnson LN. Cyclin B and cyclin A confer different substrate recognition properties on CDK2. Cell Cycle. 2007 Jun 1;6(11):1350-9. Epub 2007 Jun 11. PMID:17495531
  16. ↑ Petri ET, Errico A, Escobedo L, Hunt T, Basavappa R. The crystal structure of human cyclin B. Cell Cycle. 2007 Jun 1;6(11):1342-9. Epub 2007 Jun 14. PMID:17495533
  17. ↑ Wood DJ, Korolchuk S, Tatum NJ, Wang LZ, Endicott JA, Noble MEM, Martin MP. Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition. Cell Chem Biol. 2018 Nov 1. pii: S2451-9456(18)30375-1. doi:, 10.1016/j.chembiol.2018.10.015. PMID:30472117 doi:http://dx.doi.org/10.1016/j.chembiol.2018.10.015

Contents


6gu4, resolution 2.73Å

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