5dnr
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Aurora A Kinase in complex with ATP in space group P41212== | |
| + | <StructureSection load='5dnr' size='340' side='right' caption='[[5dnr]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5dnr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DNR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DNR FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5dnr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dnr OCA], [http://pdbe.org/5dnr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dnr RCSB], [http://www.ebi.ac.uk/pdbsum/5dnr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dnr ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the 'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases. | ||
| - | + | Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.,Janecek M, Rossmann M, Sharma P, Emery A, Huggins DJ, Stockwell SR, Stokes JE, Tan YS, Almeida EG, Hardwick B, Narvaez AJ, Hyvonen M, Spring DR, McKenzie GJ, Venkitaraman AR Sci Rep. 2016 Jun 24;6:28528. doi: 10.1038/srep28528. PMID:27339427<ref>PMID:27339427</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 5dnr" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
| + | [[Category: Almeida, E G]] | ||
| + | [[Category: Emery, A]] | ||
| + | [[Category: Hardwick, B]] | ||
| + | [[Category: Huggins, D]] | ||
[[Category: Hyvonen, M]] | [[Category: Hyvonen, M]] | ||
| - | [[Category: Narvaez, A.J]] | ||
[[Category: Janecek, M]] | [[Category: Janecek, M]] | ||
| - | [[Category: | + | [[Category: McKenzie, G]] |
| - | + | [[Category: Narvaez, A J]] | |
| - | + | ||
| - | [[Category: | + | |
[[Category: Rossmann, M]] | [[Category: Rossmann, M]] | ||
| - | [[Category: Venkitaraman, A]] | ||
| - | [[Category: Huggins, D]] | ||
| - | [[Category: Emery, A]] | ||
[[Category: Sharma, P]] | [[Category: Sharma, P]] | ||
| - | [[Category: | + | [[Category: Spring, D R]] |
| + | [[Category: Stockwell, S]] | ||
| + | [[Category: Stokes, J A]] | ||
| + | [[Category: Venkitaraman, A]] | ||
| + | [[Category: Aurora a kinase]] | ||
| + | [[Category: Mitotic kinase]] | ||
| + | [[Category: Ppi]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 15:19, 26 July 2016
Aurora A Kinase in complex with ATP in space group P41212
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Categories: Non-specific serine/threonine protein kinase | Almeida, E G | Emery, A | Hardwick, B | Huggins, D | Hyvonen, M | Janecek, M | McKenzie, G | Narvaez, A J | Rossmann, M | Sharma, P | Spring, D R | Stockwell, S | Stokes, J A | Venkitaraman, A | Aurora a kinase | Mitotic kinase | Ppi | Transferase
