4b6l

From Proteopedia

(Difference between revisions)

Current revision

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

Structural highlights

4b6l is a 1 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 1.9Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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

1 Structural highlights
2 Function
3 See Also
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4b6l"

@@ Line 3: / Line 3: @@
 <StructureSection load='4b6l' size='340' side='right'caption='[[4b6l]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4b6l]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B6L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B6L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4b6l]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B6L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B6L FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9ZP:4-[[(4R)-5-CYCLOPENTYL-4-ETHYL-3A,4-DIHYDRO-3H-[1,2,4]TRIAZOLO[4,3-F]PTERIDIN-7-YL]AMINO]-N-CYCLOPROPYL-3-METHOXY-BENZAMIDE'>9ZP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Polo_kinase Polo kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.21 2.7.11.21] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9ZP:4-[[(4R)-5-CYCLOPENTYL-4-ETHYL-3A,4-DIHYDRO-3H-[1,2,4]TRIAZOLO[4,3-F]PTERIDIN-7-YL]AMINO]-N-CYCLOPROPYL-3-METHOXY-BENZAMIDE'>9ZP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4b6l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b6l OCA], [https://pdbe.org/4b6l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b6l RCSB], [https://www.ebi.ac.uk/pdbsum/4b6l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b6l ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/PLK3_HUMAN 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.<ref>PMID:12242661</ref> <ref>PMID:9353331</ref> <ref>PMID:10557092</ref> <ref>PMID:11156373</ref> <ref>PMID:11447225</ref> <ref>PMID:11551930</ref> <ref>PMID:11971976</ref> <ref>PMID:14980500</ref> <ref>PMID:14968113</ref> <ref>PMID:15021912</ref> <ref>PMID:16478733</ref> <ref>PMID:16481012</ref> <ref>PMID:17804415</ref> <ref>PMID:17264206</ref> <ref>PMID:18062778</ref> <ref>PMID:18650425</ref> <ref>PMID:19490146</ref> <ref>PMID:19103756</ref> <ref>PMID:20889502</ref> <ref>PMID:20940307</ref> <ref>PMID:21098032</ref> <ref>PMID:21840391</ref> <ref>PMID:21376736</ref> <ref>PMID:21264284</ref>
+[https://www.uniprot.org/uniprot/PLK3_HUMAN 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.<ref>PMID:12242661</ref> <ref>PMID:9353331</ref> <ref>PMID:10557092</ref> <ref>PMID:11156373</ref> <ref>PMID:11447225</ref> <ref>PMID:11551930</ref> <ref>PMID:11971976</ref> <ref>PMID:14980500</ref> <ref>PMID:14968113</ref> <ref>PMID:15021912</ref> <ref>PMID:16478733</ref> <ref>PMID:16481012</ref> <ref>PMID:17804415</ref> <ref>PMID:17264206</ref> <ref>PMID:18062778</ref> <ref>PMID:18650425</ref> <ref>PMID:19490146</ref> <ref>PMID:19103756</ref> <ref>PMID:20889502</ref> <ref>PMID:20940307</ref> <ref>PMID:21098032</ref> <ref>PMID:21840391</ref> <ref>PMID:21376736</ref> <ref>PMID:21264284</ref>
 ==See Also==
@@ Line 17: / Line 17: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Polo kinase]]
+[[Category: Brown K]]
-[[Category: Brown, K]]
+[[Category: Charrier JD]]
-[[Category: Charrier, J D]]
+[[Category: Durrant S]]
-[[Category: Durrant, S]]
+[[Category: Griffiths M]]
-[[Category: Griffiths, M]]
+[[Category: Hudson C]]
-[[Category: Hudson, C]]
+[[Category: Kay D]]
-[[Category: Kay, D]]
+[[Category: Knegtel R]]
-[[Category: Knegtel, R]]
+[[Category: ODonnell M]]
-[[Category: ODonnell, M]]
+[[Category: Pierard F]]
-[[Category: Pierard, F]]
+[[Category: Twin H]]
-[[Category: Twin, H]]
+[[Category: Weber P]]
-[[Category: Weber, P]]
+[[Category: Young S]]
-[[Category: Young, S]]
-[[Category: Kinase inhibitor]]
-[[Category: Transferase]]
-[[Category: Water-mediated h-bond]]

4b6l

From Proteopedia

Current revision

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

Structural highlights

Function

See Also

References

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