|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='6f7b' size='340' side='right'caption='[[6f7b]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='6f7b' size='340' side='right'caption='[[6f7b]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6f7b]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F7B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F7B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6f7b]] 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=6F7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F7B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CVQ:2-[3,5-bis(fluoranyl)-4-[[3-[5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl]indazol-1-yl]methyl]phenoxy]ethanol'>CVQ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CVQ:2-[3,5-bis(fluoranyl)-4-[[3-[5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl]indazol-1-yl]methyl]phenoxy]ethanol'>CVQ</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BUB1, BUB1L ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6f7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f7b OCA], [https://pdbe.org/6f7b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f7b RCSB], [https://www.ebi.ac.uk/pdbsum/6f7b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f7b ProSAT]</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=6f7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f7b OCA], [http://pdbe.org/6f7b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f7b RCSB], [http://www.ebi.ac.uk/pdbsum/6f7b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f7b ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BUB1_HUMAN BUB1_HUMAN]] Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Plays an important role in defining SGOL1 localization and thereby affects sister chromatid cohesion. Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.<ref>PMID:10198256</ref> <ref>PMID:15020684</ref> <ref>PMID:15525512</ref> <ref>PMID:15723797</ref> <ref>PMID:16760428</ref> <ref>PMID:17158872</ref> <ref>PMID:19487456</ref> | + | [https://www.uniprot.org/uniprot/BUB1_HUMAN BUB1_HUMAN] Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Plays an important role in defining SGOL1 localization and thereby affects sister chromatid cohesion. Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.<ref>PMID:10198256</ref> <ref>PMID:15020684</ref> <ref>PMID:15525512</ref> <ref>PMID:15723797</ref> <ref>PMID:16760428</ref> <ref>PMID:17158872</ref> <ref>PMID:19487456</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 6f7b" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6f7b" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | [[Category: Bone W]] |
| - | [[Category: Ahsen, O von]]
| + | [[Category: Brands M]] |
| - | [[Category: Bone, W]] | + | [[Category: Briem H]] |
| - | [[Category: Brands, M]] | + | [[Category: Cleve A]] |
| - | [[Category: Briem, H]] | + | [[Category: Fernandez-Montalvan A]] |
| - | [[Category: Cleve, A]] | + | [[Category: Hitchcock M]] |
| - | [[Category: Fernandez-Montalvan, A]] | + | [[Category: Holton SJ]] |
| - | [[Category: Hitchcock, M]] | + | [[Category: Johanssen J]] |
| - | [[Category: Holton, S J]] | + | [[Category: Mengel A]] |
| - | [[Category: Johanssen, J]] | + | [[Category: Moenning U]] |
| - | [[Category: Mengel, A]] | + | [[Category: Mumberg D]] |
| - | [[Category: Moenning, U]] | + | [[Category: Prechtl S]] |
| - | [[Category: Mumberg, D]] | + | [[Category: Puetter V]] |
| - | [[Category: Nussbaum, F von]]
| + | [[Category: Schroeder J]] |
| - | [[Category: Prechtl, S]] | + | [[Category: Siemeister G]] |
| - | [[Category: Puetter, V]] | + | [[Category: Ziegelbauer K]] |
| - | [[Category: Schroeder, J]] | + | [[Category: Zitzmann-Kolbe S]] |
| - | [[Category: Siemeister, G]] | + | [[Category: Von Ahsen O]] |
| - | [[Category: Ziegelbauer, K]] | + | [[Category: Von Nussbaum F]] |
| - | [[Category: Zitzmann-Kolbe, S]] | + | |
| - | [[Category: Bub1]] | + | |
| - | [[Category: Kinase inhibitor]] | + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
BUB1_HUMAN Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Plays an important role in defining SGOL1 localization and thereby affects sister chromatid cohesion. Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
PURPOSE: The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability. EXPERIMENTAL DESIGN: The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models. RESULTS: The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies. CONCLUSIONS: Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance.
Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo.,Siemeister G, Mengel A, Fernandez-Montalvan AE, Bone W, Schroder J, Zitzmann-Kolbe S, Briem H, Prechtl S, Holton SJ, Monning U, von Ahsen O, Johanssen S, Cleve A, Putter V, Hitchcock M, von Nussbaum F, Brands M, Ziegelbauer K, Mumberg D Clin Cancer Res. 2019 Feb 15;25(4):1404-1414. doi: 10.1158/1078-0432.CCR-18-0628., Epub 2018 Nov 14. PMID:30429199[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Seeley TW, Wang L, Zhen JY. Phosphorylation of human MAD1 by the BUB1 kinase in vitro. Biochem Biophys Res Commun. 1999 Apr 13;257(2):589-95. PMID:10198256 doi:http://dx.doi.org/S0006-291X(99)90514-4
- ↑ Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci. 2004 Mar 15;117(Pt 8):1577-89. PMID:15020684 doi:http://dx.doi.org/10.1242/jcs.01006
- ↑ Tang Z, Shu H, Oncel D, Chen S, Yu H. Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol Cell. 2004 Nov 5;16(3):387-97. PMID:15525512 doi:http://dx.doi.org/10.1016/j.molcel.2004.09.031
- ↑ Kitajima TS, Hauf S, Ohsugi M, Yamamoto T, Watanabe Y. Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization. Curr Biol. 2005 Feb 22;15(4):353-9. PMID:15723797 doi:http://dx.doi.org/S0960982204010267
- ↑ Qi W, Tang Z, Yu H. Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1. Mol Biol Cell. 2006 Aug;17(8):3705-16. Epub 2006 Jun 7. PMID:16760428 doi:http://dx.doi.org/10.1091/mbc.E06-03-0240
- ↑ Qi W, Yu H. KEN-box-dependent degradation of the Bub1 spindle checkpoint kinase by the anaphase-promoting complex/cyclosome. J Biol Chem. 2007 Feb 9;282(6):3672-9. Epub 2006 Dec 11. PMID:17158872 doi:http://dx.doi.org/10.1074/jbc.M609376200
- ↑ Klebig C, Korinth D, Meraldi P. Bub1 regulates chromosome segregation in a kinetochore-independent manner. J Cell Biol. 2009 Jun 1;185(5):841-58. doi: 10.1083/jcb.200902128. PMID:19487456 doi:http://dx.doi.org/10.1083/jcb.200902128
- ↑ Siemeister G, Mengel A, Fernandez-Montalvan AE, Bone W, Schroder J, Zitzmann-Kolbe S, Briem H, Prechtl S, Holton SJ, Monning U, von Ahsen O, Johanssen S, Cleve A, Putter V, Hitchcock M, von Nussbaum F, Brands M, Ziegelbauer K, Mumberg D. Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo. Clin Cancer Res. 2019 Feb 15;25(4):1404-1414. doi: 10.1158/1078-0432.CCR-18-0628., Epub 2018 Nov 14. PMID:30429199 doi:http://dx.doi.org/10.1158/1078-0432.CCR-18-0628
|
