View source for 2x81


==STRUCTURE OF AURORA A IN COMPLEX WITH MLN8054==
<StructureSection load='2x81' size='340' side='right'caption='[[2x81]], [[Resolution|resolution]] 2.91&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2x81]] 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=2X81 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X81 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]] 2.91&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZZL:4-{[9-CHLORO-7-(2,6-DIFLUOROPHENYL)-5H-PYRIMIDO[5,4-D][2]BENZAZEPIN-2-YL]AMINO}BENZOIC+ACID'>ZZL</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=2x81 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x81 OCA], [https://pdbe.org/2x81 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x81 RCSB], [https://www.ebi.ac.uk/pdbsum/2x81 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x81 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AURKA_HUMAN AURKA_HUMAN] Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis.<ref>PMID:9606188</ref> <ref>PMID:11039908</ref> <ref>PMID:11551964</ref> <ref>PMID:12390251</ref> <ref>PMID:13678582</ref> <ref>PMID:14523000</ref> <ref>PMID:15147269</ref> <ref>PMID:14990569</ref> <ref>PMID:15128871</ref> <ref>PMID:14702041</ref> <ref>PMID:15987997</ref> <ref>PMID:18056443</ref> <ref>PMID:17604723</ref> <ref>PMID:17360485</ref> <ref>PMID:18615013</ref> <ref>PMID:19812038</ref> <ref>PMID:19351716</ref> <ref>PMID:19668197</ref> <ref>PMID:19357306</ref> <ref>PMID:20643351</ref> <ref>PMID:17125279</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/x8/2x81_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2x81 ConSurf].
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== Publication Abstract from PubMed ==
The Aurora kinases regulate multiple aspects of mitotic progression and their overexpression in diverse tumour types makes them appealing oncology targets. An intensive research effort over the last decade has led to the discovery of chemically distinct families of small molecule Aurora kinase inhibitors, many of which have demonstrated therapeutic potential in model systems. These agents are also important tools to help dissect signalling pathways that are orchestrated by Aurora kinases, and the anti-proliferative target of pan-Aurora inhibitors such as VX-680 has been validated using chemical genetic techniques. In many cases the non-specific nature of Aurora inhibitors towards unrelated kinases is well established, potentially broadening the spectrum of cancers to which these compounds might be applied. However, unambiguously demonstrating the molecular target(s) for clinical kinase inhibitors is an important challenge, and one that is absolutely critical for deciphering the molecular basis of compound specificity, resistance and efficacy. In this paper, we have investigated amino acid requirements for Aurora A sensitivity to the benzazepine-based Aurora inhibitor MLN8054 and the close analog MLN8237, a second-generation compound that is in phase II clinical trials. A crystallographic analysis facilitated the design and biochemical investigation of a panel of resistant Aurora A mutants, a subset of which were then selected as candidate drug-resistance targets for further evaluation. Using inducible human cell lines, we show that cells expressing near-physiological levels of a functional, but partially drug-resistant, Aurora A T217D mutant survive in the presence of MLN8054 or MLN8237, authenticating Aurora A as a critical anti-proliferative target of these compounds.

Drug-resistant Aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237.,Sloane D, Trikic M, Chu ML, Lamers M, Mason C, Mueller I, Savory W, Williams DH, Eyers PA ACS Chem Biol. 2010 Apr 28. PMID:20426425<ref>PMID:20426425</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2x81" style="background-color:#fffaf0;"></div>

==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Eyers PA]]
[[Category: Lamers M]]
[[Category: Mason CS]]
[[Category: Mueller I]]
[[Category: Savory W]]
[[Category: Williams DH]]