5g1x
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of Aurora-A kinase in complex with N-Myc== | |
| + | <StructureSection load='5g1x' size='340' side='right' caption='[[5g1x]], [[Resolution|resolution]] 1.72Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5g1x]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5G1X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5G1X FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5g1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g1x OCA], [http://pdbe.org/5g1x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5g1x RCSB], [http://www.ebi.ac.uk/pdbsum/5g1x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5g1x ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/MYCN_HUMAN MYCN_HUMAN]] Unilateral retinoblastoma;Neuroblastoma;Feingold syndrome type 1. Amplification of the N-MYC gene is associated with a variety of human tumors, most frequently neuroblastoma, where the level of amplification appears to increase as the tumor progresses.<ref>PMID:2834684</ref> The disease is caused by mutations affecting the gene represented in this entry. | ||
| + | == 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> [[http://www.uniprot.org/uniprot/MYCN_HUMAN MYCN_HUMAN]] Positively regulates the transcription of NCYM in neuroblastoma cells (PubMed:24391509).<ref>PMID:24391509</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turnover by the ubiquitin-proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by the E3 ubiquitin ligase SCFFbxW7 However, N-Myc protein (the product of the MYCN oncogene) is stabilized in neuroblastoma by the protein kinase Aurora-A in a manner that is sensitive to certain Aurora-A-selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxW7 We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72-A resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with the binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxW7 to disfavor the generation of Lys48-linked polyubiquitin chains. | ||
| - | + | Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors.,Richards MW, Burgess SG, Poon E, Carstensen A, Eilers M, Chesler L, Bayliss R Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):13726-13731. Epub 2016 Nov 11. PMID:27837025<ref>PMID:27837025</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | [[Category: | + | <div class="pdbe-citations 5g1x" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Bayliss, R]] | [[Category: Bayliss, R]] | ||
| - | [[Category: Richards, M | + | [[Category: Burgess, S G]] |
| + | [[Category: Richards, M W]] | ||
| + | [[Category: Aurora]] | ||
| + | [[Category: Aurora-a]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Myc]] | ||
| + | [[Category: N-myc]] | ||
| + | [[Category: Neuroblastoma]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 03:24, 10 December 2016
Crystal structure of Aurora-A kinase in complex with N-Myc
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