4b6l

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Template:STRUCTURE 4b6l

Contents

Discovery of Oral Polo-Like Kinase (PLK) Inhibitors with Enhanced Selectivity Profile using Residue Targeted Drug Design

Function

[PLK3_HUMAN] Serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly. Polo-like kinases act by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates ATF2, BCL2L1, CDC25A, CDC25C, CHEK2, HIF1A, JUN, p53/TP53, p73/TP73, PTEN, TOP2A and VRK1. Involved in cell cycle regulation: required for entry into S phase and cytokinesis. Phosphorylates BCL2L1, leading to regulate the G2 checkpoint and progression to cytokinesis during mitosis. Plays a key role in response to stress: rapidly activated upon stress stimulation, such as ionizing radiation, reactive oxygen species (ROS), hyperosmotic stress, UV irradiation and hypoxia. Involved in DNA damage response and G1/S transition checkpoint by phosphorylating CDC25A, p53/TP53 and p73/TP73. Phosphorylates p53/TP53 in response to reactive oxygen species (ROS), thereby promoting p53/TP53-mediated apoptosis. Phosphorylates CHEK2 in response to DNA damage, promoting the G2/M transition checkpoint. Phosphorylates the transcription factor p73/TP73 in response to DNA damage, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates HIF1A and JUN is response to hypoxia. Phosphorylates ATF2 following hyperosmotic stress in corneal epithelium. Also involved in Golgi disassembly during the cell cycle: part of a MEK1/MAP2K1-dependent pathway that induces Golgi fragmentation during mitosis by mediating phosphorylation of VRK1. May participate in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation, via its interaction with CIB1.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]

About this Structure

4b6l is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  1. ↑ Bahassi el M, Conn CW, Myer DL, Hennigan RF, McGowan CH, Sanchez Y, Stambrook PJ. Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways. Oncogene. 2002 Sep 26;21(43):6633-40. PMID:12242661 doi:10.1038/sj.onc.1205850
  2. ↑ Ouyang B, Pan H, Lu L, Li J, Stambrook P, Li B, Dai W. Human Prk is a conserved protein serine/threonine kinase involved in regulating M phase functions. J Biol Chem. 1997 Nov 7;272(45):28646-51. PMID:9353331
  3. ↑ Ouyang B, Li W, Pan H, Meadows J, Hoffmann I, Dai W. The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. Oncogene. 1999 Oct 28;18(44):6029-36. PMID:10557092 doi:10.1038/sj.onc.1202983
  4. ↑ Conn CW, Hennigan RF, Dai W, Sanchez Y, Stambrook PJ. Incomplete cytokinesis and induction of apoptosis by overexpression of the mammalian polo-like kinase, Plk3. Cancer Res. 2000 Dec 15;60(24):6826-31. PMID:11156373
  5. ↑ Xie S, Wang Q, Wu H, Cogswell J, Lu L, Jhanwar-Uniyal M, Dai W. Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3. J Biol Chem. 2001 Sep 28;276(39):36194-9. Epub 2001 Jul 10. PMID:11447225 doi:10.1074/jbc.M104157200
  6. ↑ Xie S, Wu H, Wang Q, Cogswell JP, Husain I, Conn C, Stambrook P, Jhanwar-Uniyal M, Dai W. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J Biol Chem. 2001 Nov 16;276(46):43305-12. Epub 2001 Sep 10. PMID:11551930 doi:10.1074/jbc.M106050200
  7. ↑ Wang Q, Xie S, Chen J, Fukasawa K, Naik U, Traganos F, Darzynkiewicz Z, Jhanwar-Uniyal M, Dai W. Cell cycle arrest and apoptosis induced by human Polo-like kinase 3 is mediated through perturbation of microtubule integrity. Mol Cell Biol. 2002 May;22(10):3450-9. PMID:11971976
  8. ↑ Ruan Q, Wang Q, Xie S, Fang Y, Darzynkiewicz Z, Guan K, Jhanwar-Uniyal M, Dai W. Polo-like kinase 3 is Golgi localized and involved in regulating Golgi fragmentation during the cell cycle. Exp Cell Res. 2004 Mar 10;294(1):51-9. PMID:14980500 doi:10.1016/j.yexcr.2003.10.022
  9. ↑ Bahassi el M, Hennigan RF, Myer DL, Stambrook PJ. Cdc25C phosphorylation on serine 191 by Plk3 promotes its nuclear translocation. Oncogene. 2004 Apr 8;23(15):2658-63. PMID:14968113 doi:10.1038/sj.onc.1207425
  10. ↑ Xie S, Wang Q, Ruan Q, Liu T, Jhanwar-Uniyal M, Guan K, Dai W. MEK1-induced Golgi dynamics during cell cycle progression is partly mediated by Polo-like kinase-3. Oncogene. 2004 May 6;23(21):3822-9. PMID:15021912 doi:10.1038/sj.onc.1207479
  11. ↑ Jiang N, Wang X, Jhanwar-Uniyal M, Darzynkiewicz Z, Dai W. Polo box domain of Plk3 functions as a centrosome localization signal, overexpression of which causes mitotic arrest, cytokinesis defects, and apoptosis. J Biol Chem. 2006 Apr 14;281(15):10577-82. Epub 2006 Feb 14. PMID:16478733 doi:10.1074/jbc.M513156200
  12. ↑ Bahassi el M, Myer DL, McKenney RJ, Hennigan RF, Stambrook PJ. Priming phosphorylation of Chk2 by polo-like kinase 3 (Plk3) mediates its full activation by ATM and a downstream checkpoint in response to DNA damage. Mutat Res. 2006 Apr 11;596(1-2):166-76. Epub 2006 Feb 14. PMID:16481012 doi:10.1016/j.mrfmmm.2005.12.002
  13. ↑ Wang L, Dai W, Lu L. Stress-induced c-Jun activation mediated by Polo-like kinase 3 in corneal epithelial cells. J Biol Chem. 2007 Nov 2;282(44):32121-7. Epub 2007 Sep 5. PMID:17804415 doi:10.1074/jbc.M702791200
  14. ↑ Zimmerman WC, Erikson RL. Polo-like kinase 3 is required for entry into S phase. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1847-52. Epub 2007 Jan 30. PMID:17264206 doi:10.1073/pnas.0610856104
  15. ↑ Iida M, Matsuda M, Komatani H. Plk3 phosphorylates topoisomerase IIalpha at Thr(1342), a site that is not recognized by Plk1. Biochem J. 2008 Apr 1;411(1):27-32. PMID:18062778 doi:10.1042/BJ20071394
  16. ↑ Wang L, Gao J, Dai W, Lu L. Activation of Polo-like kinase 3 by hypoxic stresses. J Biol Chem. 2008 Sep 19;283(38):25928-35. doi: 10.1074/jbc.M801326200. Epub 2008, Jul 23. PMID:18650425 doi:10.1074/jbc.M801326200
  17. ↑ Sang M, Ando K, Okoshi R, Koida N, Li Y, Zhu Y, Shimozato O, Geng C, Shan B, Nakagawara A, Ozaki T. Plk3 inhibits pro-apoptotic activity of p73 through physical interaction and phosphorylation. Genes Cells. 2009 Jul;14(7):775-88. doi: 10.1111/j.1365-2443.2009.01309.x. Epub, 2009 May 28. PMID:19490146 doi:10.1111/j.1365-2443.2009.01309.x
  18. ↑ Lopez-Sanchez I, Sanz-Garcia M, Lazo PA. Plk3 interacts with and specifically phosphorylates VRK1 in Ser342, a downstream target in a pathway that induces Golgi fragmentation. Mol Cell Biol. 2009 Mar;29(5):1189-201. doi: 10.1128/MCB.01341-08. Epub 2008 Dec , 22. PMID:19103756 doi:10.1128/MCB.01341-08
  19. ↑ Xu D, Yao Y, Lu L, Costa M, Dai W. Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha. J Biol Chem. 2010 Dec 10;285(50):38944-50. doi: 10.1074/jbc.M110.160325. Epub, 2010 Oct 1. PMID:20889502 doi:10.1074/jbc.M110.160325
  20. ↑ Xu D, Yao Y, Jiang X, Lu L, Dai W. Regulation of PTEN stability and activity by Plk3. J Biol Chem. 2010 Dec 17;285(51):39935-42. doi: 10.1074/jbc.M110.166462. Epub, 2010 Oct 12. PMID:20940307 doi:10.1074/jbc.M110.166462
  21. ↑ Wang L, Payton R, Dai W, Lu L. Hyperosmotic stress-induced ATF-2 activation through Polo-like kinase 3 in human corneal epithelial cells. J Biol Chem. 2011 Jan 21;286(3):1951-8. doi: 10.1074/jbc.M110.166009. Epub 2010, Nov 22. PMID:21098032 doi:10.1074/jbc.M110.166009
  22. ↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
  23. ↑ Myer DL, Robbins SB, Yin M, Boivin GP, Liu Y, Greis KD, Bahassi el M, Stambrook PJ. Absence of polo-like kinase 3 in mice stabilizes Cdc25A after DNA damage but is not sufficient to produce tumors. Mutat Res. 2011 Sep 1;714(1-2):1-10. doi: 10.1016/j.mrfmmm.2011.02.006. Epub 2011, Mar 3. PMID:21376736 doi:10.1016/j.mrfmmm.2011.02.006
  24. ↑ Kostyak JC, Naik UP. Calcium- and integrin-binding protein 1 regulates endomitosis and its interaction with Polo-like kinase 3 is enhanced in endomitotic Dami cells. PLoS One. 2011 Jan 14;6(1):e14513. doi: 10.1371/journal.pone.0014513. PMID:21264284 doi:10.1371/journal.pone.0014513

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