View source for 5eyk


==CRYSTAL STRUCTURE OF AURORA B IN COMPLEX WITH BI 847325==
<StructureSection load='5eyk' size='340' side='right'caption='[[5eyk]], [[Resolution|resolution]] 1.93&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5eyk]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EYK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EYK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.93&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5U5:3-[(3~{Z})-3-[[[4-[(DIMETHYLAMINO)METHYL]PHENYL]AMINO]-PHENYL-METHYLIDENE]-2-OXIDANYLIDENE-1~{H}-INDOL-6-YL]-~{N}-ETHYL-PROP-2-YNAMIDE'>5U5</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=5eyk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eyk OCA], [https://pdbe.org/5eyk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eyk RCSB], [https://www.ebi.ac.uk/pdbsum/5eyk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eyk ProSAT]</span></td></tr>
</table>
== Function ==
[https://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> 
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== Publication Abstract from PubMed ==
Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases (AK). Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, while in KRAS-mutant cells, MEK inhibition required higher concentrations than AK inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF mutant models, but of AK in KRAS-mutant models. Inhibition of both MEK and AK in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics and efficacy of BI 847325 in cancer patients.

Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-competitive Inhibitor of MEK and Aurora Kinases.,Sini P, Gurtler U, Zahn SK, Baumann C, Rudolph D, Baumgartinger R, Strauss E, Haslinger C, Tontsch-Grunt U, Waizenegger IC, Solca F, Bader G, Zoephel A, Treu M, Reiser U, Garin-Chesa P, Boehmelt G, Kraut N, Quant J, Adolf GR Mol Cancer Ther. 2016 Aug 5. pii: molcanther.0066.2016. PMID:27496137<ref>PMID:27496137</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5eyk" style="background-color:#fffaf0;"></div>

==See Also==
*[[Centromere protein 3D structure|Centromere protein 3D structure]]
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Xenopus laevis]]
[[Category: Bader G]]
[[Category: Zoephel A]]