2np8

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(New page: 200px<br /> <applet load="2np8" size="450" color="white" frame="true" align="right" spinBox="true" caption="2np8, resolution 2.25&Aring;" /> '''Structural Basis fo...)
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[[Image:2np8.gif|left|200px]]<br />
 
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<applet load="2np8" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2np8, resolution 2.25&Aring;" />
 
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'''Structural Basis for the Inhibition of Aurora A Kinase by a Novel Class of High Affinity Disubstituted Pyrimidine Inhibitors'''<br />
 
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==Overview==
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==Structural Basis for the Inhibition of Aurora A Kinase by a Novel Class of High Affinity Disubstituted Pyrimidine Inhibitors==
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The 2.25 A crystal structure of a complex of Aurora A kinase (AIKA) with, cyclopropanecarboxylic, acid-(3-(4-(3-trifluoromethyl-phenylamino)-pyrimidin-2-ylamino)-phenyl)-am, ide 1 is described here. The inhibitor binding mode is novel, with the, cyclopropanecarboxylic acid moiety directed towards the solvent exposed, region of the ATP-binding pocket, and several induced structural changes, in the active-site compared with other published AIK structures. This, structure provides context for the available SAR data on this compound, class, and could be exploited for the design of analogs with increased, affinity and selectivity for AIK.
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<StructureSection load='2np8' size='340' side='right'caption='[[2np8]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2np8]] 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=2NP8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NP8 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]] 2.25&#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=CC3:N-{3-[(4-{[3-(TRIFLUOROMETHYL)PHENYL]AMINO}PYRIMIDIN-2-YL)AMINO]PHENYL}CYCLOPROPANECARBOXAMIDE'>CC3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2np8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2np8 OCA], [https://pdbe.org/2np8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2np8 RCSB], [https://www.ebi.ac.uk/pdbsum/2np8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2np8 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/np/2np8_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=2np8 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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The 2.25 A crystal structure of a complex of Aurora A kinase (AIKA) with cyclopropanecarboxylic acid-(3-(4-(3-trifluoromethyl-phenylamino)-pyrimidin-2-ylamino)-phenyl)-am ide 1 is described here. The inhibitor binding mode is novel, with the cyclopropanecarboxylic acid moiety directed towards the solvent exposed region of the ATP-binding pocket, and several induced structural changes in the active-site compared with other published AIK structures. This structure provides context for the available SAR data on this compound class, and could be exploited for the design of analogs with increased affinity and selectivity for AIK.
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==Disease==
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Structural basis for the inhibition of Aurora A kinase by a novel class of high affinity disubstituted pyrimidine inhibitors.,Tari LW, Hoffman ID, Bensen DC, Hunter MJ, Nix J, Nelson KJ, McRee DE, Swanson RV Bioorg Med Chem Lett. 2007 Feb 1;17(3):688-91. Epub 2006 Nov 2. PMID:17157005<ref>PMID:17157005</ref>
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Known diseases associated with this structure: Colon cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603072 603072]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2NP8 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and CC3 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2NP8 OCA].
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</div>
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<div class="pdbe-citations 2np8" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Structural basis for the inhibition of Aurora A kinase by a novel class of high affinity disubstituted pyrimidine inhibitors., Tari LW, Hoffman ID, Bensen DC, Hunter MJ, Nix J, Nelson KJ, McRee DE, Swanson RV, Bioorg Med Chem Lett. 2007 Feb 1;17(3):688-91. Epub 2006 Nov 2. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17157005 17157005]
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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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<references/>
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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: Single protein]]
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[[Category: Bensen DC]]
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[[Category: Bensen, D.C.]]
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[[Category: Hoffman ID]]
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[[Category: Hoffman, I.D.]]
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[[Category: Hunter MJ]]
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[[Category: Hunter, M.J.]]
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[[Category: McRee DE]]
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[[Category: McRee, D.E.]]
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[[Category: Nelson KJ]]
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[[Category: Nelson, K.J.]]
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[[Category: Nix J]]
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[[Category: Nix, J.]]
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[[Category: Swanson RV]]
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[[Category: Swanson, R.V.]]
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[[Category: Tari LW]]
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[[Category: Tari, L.W.]]
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[[Category: CC3]]
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[[Category: SO4]]
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[[Category: aik]]
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[[Category: aurora 2 kinase]]
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[[Category: aurora a kinase]]
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[[Category: kinase]]
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[[Category: kinase inhibitor]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:01:13 2007''
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Current revision

Structural Basis for the Inhibition of Aurora A Kinase by a Novel Class of High Affinity Disubstituted Pyrimidine Inhibitors

PDB ID 2np8

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