3coh

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[[Image:3coh.png|left|200px]]
 
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{{STRUCTURE_3coh| PDB=3coh | SCENE= }}
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==Crystal structure of Aurora-A in complex with a pentacyclic inhibitor==
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<StructureSection load='3coh' size='340' side='right'caption='[[3coh]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3coh]] 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=3COH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3COH 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]] 2.7&#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=83H:8-ETHYL-3,10,10-TRIMETHYL-4,5,6,8,10,12-HEXAHYDROPYRAZOLO[4,3 6,7]CYCLOHEPTA[1,2-B]PYRROLO[2,3-F]INDOL-9(1H)-ONE'>83H</scene></td></tr>
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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=3coh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3coh OCA], [https://pdbe.org/3coh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3coh RCSB], [https://www.ebi.ac.uk/pdbsum/3coh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3coh 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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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/co/3coh_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=3coh 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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Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 &lt; 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.
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===Crystal structure of Aurora-A in complex with a pentacyclic inhibitor===
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A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.,Rawson TE, Ruth M, Blackwood E, Burdick D, Corson L, Dotson J, Drummond J, Fields C, Georges GJ, Goller B, Halladay J, Hunsaker T, Kleinheinz T, Krell HW, Li J, Liang J, Limberg A, McNutt A, Moffat J, Phillips G, Ran Y, Safina B, Ultsch M, Walker L, Wiesmann C, Zhang B, Zhou A, Zhu BY, Ruger P, Cochran AG J Med Chem. 2008 Aug 14;51(15):4465-75. Epub 2008 Jul 17. PMID:18630890<ref>PMID:18630890</ref>
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{{ABSTRACT_PUBMED_18630890}}
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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 3coh" style="background-color:#fffaf0;"></div>
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==About this Structure==
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==See Also==
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[[3coh]] is a 2 chain structure with sequence 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=3COH OCA].
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*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:018630890</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[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: Cochran, A G.]]
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[[Category: Cochran AG]]
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[[Category: Raswson, T E.]]
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[[Category: Raswson TE]]
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[[Category: Wiesmann, C.]]
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[[Category: Wiesmann C]]
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[[Category: Atp-binding]]
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[[Category: Aurora-a]]
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[[Category: Cell cycle]]
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[[Category: Inhibitor complex]]
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[[Category: Kinase]]
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[[Category: Nucleotide-binding]]
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[[Category: Phosphoprotein]]
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[[Category: Serine/threonine-protein kinase]]
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[[Category: Transferase]]
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Current revision

Crystal structure of Aurora-A in complex with a pentacyclic inhibitor

PDB ID 3coh

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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