|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Aurora kinase selective inhibitors identified using a Taxol-induced checkpoint sensitivity screen.== | | ==Aurora kinase selective inhibitors identified using a Taxol-induced checkpoint sensitivity screen.== |
| - | <StructureSection load='3ztx' size='340' side='right' caption='[[3ztx]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='3ztx' size='340' side='right'caption='[[3ztx]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ztx]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/African_clawed_frog African clawed frog]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZTX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZTX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ztx]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/African_clawed_frog African clawed frog]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZTX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3ZTX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZTX:2-((4-(4-HYDROXYPIPERIDIN-1-YL)PHENYL)AMINO)-5,11-DIMETHYL-5H-BENZO[E]PYRIMIDO+[5,4-B][1,4]DIAZEPIN-6(11H)-ONE'>ZTX</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZTX:2-((4-(4-HYDROXYPIPERIDIN-1-YL)PHENYL)AMINO)-5,11-DIMETHYL-5H-BENZO[E]PYRIMIDO+[5,4-B][1,4]DIAZEPIN-6(11H)-ONE'>ZTX</scene></td></tr> |
| | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> |
| | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bfx|2bfx]], [[2vgo|2vgo]], [[2vrx|2vrx]], [[2vgp|2vgp]], [[2bfy|2bfy]]</td></tr> | | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bfx|2bfx]], [[2vgo|2vgo]], [[2vrx|2vrx]], [[2vgp|2vgp]], [[2bfy|2bfy]]</td></tr> |
| | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ztx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ztx OCA], [http://pdbe.org/3ztx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ztx RCSB], [http://www.ebi.ac.uk/pdbsum/3ztx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ztx ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3ztx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ztx OCA], [http://pdbe.org/3ztx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ztx RCSB], [http://www.ebi.ac.uk/pdbsum/3ztx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ztx ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| Line 23: |
Line 23: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Centromere protein|Centromere protein]] | + | *[[Centromere protein 3D structure|Centromere protein 3D structure]] |
| - | *[[Inner centromere protein|Inner centromere protein]]
| + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| - | *[[Serine/threonine protein kinase|Serine/threonine protein kinase]] | + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Line 31: |
Line 30: |
| | </StructureSection> | | </StructureSection> |
| | [[Category: African clawed frog]] | | [[Category: African clawed frog]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Non-specific serine/threonine protein kinase]] | | [[Category: Non-specific serine/threonine protein kinase]] |
| | [[Category: Gray, N]] | | [[Category: Gray, N]] |
| Structural highlights
3ztx is a 4 chain structure with sequence from African clawed frog. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| NonStd Res: | |
| Related: | 2bfx, 2vgo, 2vrx, 2vgp, 2bfy |
| Activity: | Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[AUKBA_XENLA] Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis. Required for central/midzone spindle assembly and cleavage furrow formation. Phosphorylates 'Ser-10' of histone H3 during mitosis.[1] [2] [3] [INCEA_XENLA] Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Probably acts through association with aurkb or aurkc. Seems to bind directly to microtubules.[4] [5]
Publication Abstract from PubMed
The members of the Aurora kinase family play critical roles in the regulation of the cell cycle and mitotic spindle assembly and have been intensively investigated as potential targets for a new class of anticancer drugs. We describe a new highly potent and selective class of Aurora kinase inhibitors discovered using a phenotypic cellular screen. Optimized inhibitors display many of the hallmarks of Aurora inhibition including endoreduplication, polyploidy, and loss of cell viability in cancer cells. Structure-activity relationships with respect to kinome-wide selectivity and guided by an Aurora B co-crystal structure resulted in the identification of key selectivity determinants and discovery of a subseries with selectivity toward Aurora A. A direct comparison of biochemical and cellular profiles with respect to published Aurora inhibitors including VX-680, AZD1152, MLN8054, and a pyrimidine-based compound from Genentech demonstrates that compounds 1 and 3 will become valuable additional pharmacological probes of Aurora-dependent functions.
Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen.,Kwiatkowski N, Deng X, Wang J, Tan L, Villa F, Santaguida S, Huang HC, Mitchison T, Musacchio A, Gray N ACS Chem Biol. 2012 Jan 20;7(1):185-96. Epub 2011 Oct 21. PMID:21992004[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bolton MA, Lan W, Powers SE, McCleland ML, Kuang J, Stukenberg PT. Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosphorylation. Mol Biol Cell. 2002 Sep;13(9):3064-77. PMID:12221116 doi:10.1091/mbc.E02-02-0092
- ↑ Murnion ME, Adams RR, Callister DM, Allis CD, Earnshaw WC, Swedlow JR. Chromatin-associated protein phosphatase 1 regulates aurora-B and histone H3 phosphorylation. J Biol Chem. 2001 Jul 13;276(28):26656-65. Epub 2001 May 11. PMID:11350965 doi:10.1074/jbc.M102288200
- ↑ Kelly AE, Sampath SC, Maniar TA, Woo EM, Chait BT, Funabiki H. Chromosomal enrichment and activation of the aurora B pathway are coupled to spatially regulate spindle assembly. Dev Cell. 2007 Jan;12(1):31-43. PMID:17199039 doi:10.1016/j.devcel.2006.11.001
- ↑ Bolton MA, Lan W, Powers SE, McCleland ML, Kuang J, Stukenberg PT. Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosphorylation. Mol Biol Cell. 2002 Sep;13(9):3064-77. PMID:12221116 doi:10.1091/mbc.E02-02-0092
- ↑ Kelly AE, Sampath SC, Maniar TA, Woo EM, Chait BT, Funabiki H. Chromosomal enrichment and activation of the aurora B pathway are coupled to spatially regulate spindle assembly. Dev Cell. 2007 Jan;12(1):31-43. PMID:17199039 doi:10.1016/j.devcel.2006.11.001
- ↑ Kwiatkowski N, Deng X, Wang J, Tan L, Villa F, Santaguida S, Huang HC, Mitchison T, Musacchio A, Gray N. Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen. ACS Chem Biol. 2012 Jan 20;7(1):185-96. Epub 2011 Oct 21. PMID:21992004 doi:10.1021/cb200305u
|
