4byi

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{{STRUCTURE_4byi| PDB=4byi | SCENE= }}
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==Aurora A kinase bound to a highly selective imidazopyridine inhibitor==
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===Aurora A kinase bound to a highly selective imidazopyridine inhibitor===
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<StructureSection load='4byi' size='340' side='right' caption='[[4byi]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24195668}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4byi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BYI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BYI FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FH3:(S)-N-((1-(6-CHLORO-2-(1,3-DIMETHYL-1H-PYRAZOL-4-YL)-3H-IMIDAZO[4,5-B]PYRIDIN-7-YL)PYRROLIDIN-3-YL)METHYL)ACETAMIDE'>FH3</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4byj|4byj]]</td></tr>
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<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>
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<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=4byi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4byi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4byi RCSB], [http://www.ebi.ac.uk/pdbsum/4byi PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.
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==Function==
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Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5-b]pyridine Derivatives as Highly Selective Inhibitors of Aurora-A Kinase in Cells.,Bavetsias V, Faisal A, Crumpler S, Brown N, Kosmopoulou M, Joshi A, Atrash B, Perez-Fuertes Y, Schmitt JA, Boxall KJ, Burke R, Sun C, Avery S, Bush K, Henley A, Raynaud FI, Workman P, Bayliss R, Linardopoulos S, Blagg J J Med Chem. 2013 Nov 6. PMID:24195668<ref>PMID:24195668</ref>
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[[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>
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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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[[4byi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BYI OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:024195668</ref><references group="xtra"/><references/>
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*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Bayliss, R.]]
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[[Category: Bayliss, R]]
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[[Category: Joshi, A.]]
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[[Category: Joshi, A]]
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[[Category: Kosmopoulou, M.]]
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[[Category: Kosmopoulou, M]]
[[Category: Cell cycle]]
[[Category: Cell cycle]]
[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 16:46, 21 December 2014

Aurora A kinase bound to a highly selective imidazopyridine inhibitor

4byi, resolution 2.60Å

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