7ayh
From Proteopedia
(Difference between revisions)
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==Crystal structure of Aurora A in complex with 7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-one derivative (compound 2c)== | ==Crystal structure of Aurora A in complex with 7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-one derivative (compound 2c)== | ||
| - | <StructureSection load='7ayh' size='340' side='right'caption='[[7ayh]]' scene=''> | + | <StructureSection load='7ayh' size='340' side='right'caption='[[7ayh]], [[Resolution|resolution]] 2.80Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AYH OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[7ayh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AYH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AYH FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S9H:7-[2-[(4-methoxyphenyl)amino]pyrimidin-4-yl]-1,3,4,5-tetrahydro-1-benzazepin-2-one'>S9H</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AURKA, AIK, AIRK1, ARK1, AURA, AYK1, BTAK, IAK1, STK15, STK6 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7ayh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ayh OCA], [https://pdbe.org/7ayh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ayh RCSB], [https://www.ebi.ac.uk/pdbsum/7ayh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ayh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines. | ||
| + | |||
| + | 7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a "Cut and Glue" Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors.,Karatas M, Chaikuad A, Berger B, Kubbutat MHG, Totzke F, Knapp S, Kunick C Molecules. 2021 Mar 14;26(6). pii: molecules26061611. doi:, 10.3390/molecules26061611. PMID:33799460<ref>PMID:33799460</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7ayh" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Chaikuad A]] | + | [[Category: Non-specific serine/threonine protein kinase]] |
| - | [[Category: Karatas M]] | + | [[Category: Chaikuad, A]] |
| - | [[Category: Knapp S]] | + | [[Category: Karatas, M]] |
| - | [[Category: Kunick C]] | + | [[Category: Knapp, S]] |
| + | [[Category: Kunick, C]] | ||
| + | [[Category: Structural genomic]] | ||
| + | [[Category: Aurora kinase]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Kinase inhibitor]] | ||
| + | [[Category: Sgc]] | ||
| + | [[Category: Stk6]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 07:00, 14 April 2021
Crystal structure of Aurora A in complex with 7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-one derivative (compound 2c)
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