3e5a

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[[Image:3e5a.jpg|left|200px]]
 
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==Crystal structure of Aurora A in complex with VX-680 and TPX2==
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The line below this paragraph, containing "STRUCTURE_3e5a", creates the "Structure Box" on the page.
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<StructureSection load='3e5a' size='340' side='right'caption='[[3e5a]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3e5a]] is a 2 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=3E5A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3E5A FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=VX6:CYCLOPROPANECARBOXYLIC+ACID+{4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE'>VX6</scene></td></tr>
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{{STRUCTURE_3e5a| PDB=3e5a | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3e5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3e5a OCA], [https://pdbe.org/3e5a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3e5a RCSB], [https://www.ebi.ac.uk/pdbsum/3e5a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3e5a ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/e5/3e5a_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3e5a ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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VX-680, also known as MK-0457, is an ATP-competitive small molecule inhibitor of the Aurora kinases that has entered phase II clinical trials for the treatment of cancer. We have solved the cocrystal structure of AurA/TPX2/VX-680 at 2.3 A resolution. In the crystal structure, VX-680 binds to the active conformation of AurA. The glycine-rich loop in AurA adopts a unique bent conformation, forming a pi-pi interaction with the phenyl group of VX-680. In contrast, in the published AurA/VX-680 structure, VX-680 binds to AurA in the inactive conformation, interacting with a hydrophobic pocket only present in the inactive conformation. These data suggest that TPX2, a protein cofactor, can alter the binding mode of VX-680 with AurA. More generally, the presence of physiologically relevant cofactor proteins can alter the kinetics, binding interactions, and inhibition of enzymes, and studies with these multiprotein complexes may be beneficial to the discovery and optimization of enzyme inhibitors as therapeutic agents.
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===Crystal structure of Aurora A in complex with VX-680 and TPX2===
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Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2.,Zhao B, Smallwood A, Yang J, Koretke K, Nurse K, Calamari A, Kirkpatrick RB, Lai Z Protein Sci. 2008 Oct;17(10):1791-7. Epub 2008 Jul 28. PMID:18662907<ref>PMID:18662907</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3e5a" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_18662907}}, adds the Publication Abstract to the page
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*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 18662907 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_18662907}}
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__TOC__
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</StructureSection>
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==About this Structure==
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3E5A is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3E5A OCA].
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==Reference==
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Modulation of kinase-inhibitor interactions by auxiliary protein binding: crystallography studies on Aurora A interactions with VX-680 and with TPX2., Zhao B, Smallwood A, Yang J, Koretke K, Nurse K, Calamari A, Kirkpatrick RB, Lai Z, Protein Sci. 2008 Oct;17(10):1791-7. Epub 2008 Jul 28. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18662907 18662907]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Large Structures]]
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[[Category: Protein complex]]
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[[Category: Lai Z]]
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[[Category: Lai, Z.]]
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[[Category: Smallwood A]]
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[[Category: Smallwood, A.]]
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[[Category: Zhao B]]
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[[Category: Zhao, B.]]
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[[Category: Atp-binding]]
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[[Category: Aurora some]]
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[[Category: Cell cycle]]
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[[Category: Cofactor]]
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[[Category: Inhibitor]]
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[[Category: Nucleotide-binding]]
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[[Category: Nucleus]]
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[[Category: Phosphoprotein]]
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[[Category: Phosphorylation]]
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[[Category: Polymorphism]]
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[[Category: Serine/threonine-protein kinase]]
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[[Category: Tpx2]]
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[[Category: Transferase]]
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[[Category: Vx-680]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Oct 29 11:00:55 2008''
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Current revision

Crystal structure of Aurora A in complex with VX-680 and TPX2

PDB ID 3e5a

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