2vgp: Difference between revisions

Revision as of 19:01, 24 December 2014

CRYSTAL STRUCTURE OF AURORA B KINASE IN COMPLEX WITH A AMINOTHIAZOLE INHIBITOR

Structural highlights

2vgp is a 4 chain structure with sequence from Xenopus laevis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	AD6
NonStd Res:	TPO
Related:	2bfx, 2bfy, 2vgo
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, RCSB, PDBsum

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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Aurora family kinases regulate important events during mitosis including centrosome maturation and separation, mitotic spindle assembly, and chromosome segregation. Misregulation of Aurora kinases due to genetic amplification and protein overexpression results in aneuploidy and may contribute to tumorigenesis. Here we report the discovery of new small molecule aminothiazole inhibitors of Aurora kinases with exceptional kinase selectivity and report a 1.7 A cocrystal structure with the Aurora B:INCENP complex from Xenopus laevis. The compounds recapitulate the hallmarks of Aurora kinase inhibition, including decreased histone H3 serine 10 phosphorylation, failure to complete cytokinesis, and endoreduplication.

Discovery of selective aminothiazole aurora kinase inhibitors.,Andersen CB, Wan Y, Chang JW, Riggs B, Lee C, Liu Y, Sessa F, Villa F, Kwiatkowski N, Suzuki M, Nallan L, Heald R, Musacchio A, Gray NS ACS Chem Biol. 2008 Mar 20;3(3):180-92. Epub 2008 Feb 29. PMID:18307303^[6]

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

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
↑ Andersen CB, Wan Y, Chang JW, Riggs B, Lee C, Liu Y, Sessa F, Villa F, Kwiatkowski N, Suzuki M, Nallan L, Heald R, Musacchio A, Gray NS. Discovery of selective aminothiazole aurora kinase inhibitors. ACS Chem Biol. 2008 Mar 20;3(3):180-92. Epub 2008 Feb 29. PMID:18307303 doi:10.1021/cb700200w

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] Andersen CB, Wan Y, Chang JW, Riggs B, Lee C, Liu Y, Sessa F, Villa F, Kwiatkowski N, Suzuki M, Nallan L, Heald R, Musacchio A, Gray NS. Discovery of selective aminothiazole aurora kinase inhibitors. ACS Chem Biol. 2008 Mar 20;3(3):180-92. Epub 2008 Feb 29. PMID:18307303 doi:10.1021/cb700200w

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[2]

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[4]

[5]

[6]

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2vgp]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VGP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VGP FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AD6:4-[(5-BROMO-1,3-THIAZOL-2-YL)AMINO]-N-METHYLBENZAMIDE'>AD6</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AD6:4-[(5-BROMO-1,3-THIAZOL-2-YL)AMINO]-N-METHYLBENZAMIDE'>AD6</scene></td></tr>
-<tr><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><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bfx|2bfx]], [[2bfy|2bfy]], [[2vgo|2vgo]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2bfx|2bfx]], [[2bfy|2bfy]], [[2vgo|2vgo]]</td></tr>
-<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vgp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vgp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2vgp RCSB], [http://www.ebi.ac.uk/pdbsum/2vgp PDBsum]</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=2vgp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vgp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2vgp RCSB], [http://www.ebi.ac.uk/pdbsum/2vgp PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/AUKBA_XENLA 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.<ref>PMID:12221116</ref> <ref>PMID:11350965</ref> <ref>PMID:17199039</ref>  [[http://www.uniprot.org/uniprot/INCEA_XENLA 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.<ref>PMID:12221116</ref> <ref>PMID:17199039</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 37: / Line 39: @@
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Xenopus laevis]]
-[[Category: Andersen, C B.]]
+[[Category: Andersen, C B]]
-[[Category: Chang, J W.]]
+[[Category: Chang, J W]]
-[[Category: Gray, N S.]]
+[[Category: Gray, N S]]
-[[Category: Lee, C.]]
+[[Category: Lee, C]]
-[[Category: Liu, Y.]]
+[[Category: Liu, Y]]
-[[Category: Musacchio, A.]]
+[[Category: Musacchio, A]]
-[[Category: Nallan, L.]]
+[[Category: Nallan, L]]
-[[Category: Sessa, F.]]
+[[Category: Sessa, F]]
-[[Category: Villa, F.]]
+[[Category: Villa, F]]
-[[Category: Wan, Y.]]
+[[Category: Wan, Y]]
 [[Category: Aminothiazole]]
 [[Category: Atp-binding]]

2vgp: Difference between revisions

Revision as of 19:01, 24 December 2014

CRYSTAL STRUCTURE OF AURORA B KINASE IN COMPLEX WITH A AMINOTHIAZOLE INHIBITOR

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

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